Alk protein degradation agent and anti-tumor application thereof

ABSTRACT

A compound of formula (I) and its antitumor application are disclosed. The compounds of formula (I) have degradation and inhibitory effects on ALK target proteins. They are mainly composed of four parts: the first part, ALK-TKI, being compounds with ALK tyrosine kinase inhibitory activity; the second part, LIN, being different kinds of linker (Linker); the third part, the ULM, being a small molecule ligand (ULM, ubiquitin ligase binding moiety) with ubiquitination of VHL, CRBN or other proteases; and the fourth part, the group A, being a carbonyl group or absent, which covalently bond ALK-TKI to LIN, wherein LIN and ULM are covalently bonded. A series of compounds designed and synthesized by the present disclosure have wide pharmacological activities, have functions of degrading ALK protein and inhibiting ALK activity, and can be used for related tumor treatment.

FIELD

The present disclosure relates generally to compounds of formula (I) for cancer prevention and therapy, and their use in anti-cancer therapy, especially against cancer-related proteins including ALK, MET, ROS1, EGFR and FLT3.

BACKGROUND

Lung cancer is the leading cause of cancer related death in China and the world wide. In China, the incidence of lung cancer is already surpassed other types of cancer, and each year there are about 800,000 people died from lung cancer. The five-year survival rate of lung cancer is also very low, and it is only about 17%. And this rate have doesn't change too much since 70s in the last century. This is because traditional chemotherapy and radio-therapy killed normal cells together with cancer cells, which causes decreased immunity and dysfunction of patients physiology. Recently precision medicine provides targeted therapy to patients with specific driver genes which greatly reduced the toxic effect or traditional chemotherapy and radio-therapy and greatly improved patients quality of life.

Treating ALK (Anaplastic Lymphoma Kinase) mutation positive non-small cell lung cancer with specific small molecular tyrosine kinsae inhibitors greatly improved the efficacy of cancer therapy and patient quality of life. In lung cancer, patients with EML4-ALK gene fusion are about 3-7% of the total number of non-small cell lung cancer patients. The incidence ratio has no significant difference in Asian and western caucasion populations. In clinics, such mutations are often observed in young non-smoker patients (Soda et al. 2007; Nishio et al. 2017; Chan et al., 2017). ALK is a typrosine kinase. Gene fusion of this gene is a strong cancer driver gene which was firstly discovered in anaplastic large cell lymphoma patients, and later were found in many other diseases including diffused large B-cell lymphoma and Inflammatory Myofibroblastic Tumor (IMT) (Wellmann et al., 1997). ALK forms fusion genes with different partners and leads to consitutively activated ALK kinase activities to transform normal cells become cancer cells (Soda et al., 2007; Choi et al., 2008; Cha et al., 2016). In lung cancer, the major fusion partner with ALK is Echinoderm microtubule-associated protein-like 4, EML4. ALK can form fusion proteins with many other different partners, such as KIF5B, to drive cancer formation (Takeuchi et al. 2008). Such ALK fusion positive cancer cells are highly dependent on ALK kinase activities and inhibition of ALK kinase activity leads to death of these cells. Several ALK kinase inhibitors have been approved to treat ALKmutant positive cancer. In 2011, Crizotinib developed by Pfizer was approved by FDA to treat ALK positive non-small cell lung cancer. In 2016, Crizotinib was approved to treat non-small cell lung cancer patients with ROS1 (c-ros oncogene 1 receptor tyrosine kinase,c-ros) mutation. With this drug, the progression free survival of the patients was increased to about 10 months (Nishio et al, 2017). Regardless of with or without pretreatment, Crizotinib showed greater benefit to patients. It increased median progression free survival from 7.2 months with chemotherapy to 9.6 months, and which was increased to 13.6 months in Asian patients (Nishio et al., 2017). And the objective response rate was increased from 20% to 65% comparing those treated with chemotherapy. Treating ALK fusion positive patients with specific tyrosing kinase inhibitors provides great benefit to patients in clinics and it made a new milestone in lung cancer therapy.

There are more than 20 different genes were reported serve as partners of ALK. These different forms of ALK fusion proteins are also highly depend on ALK kinase activity and sensitive to ALK kinase inhibitors. In addition, ALK gene fusions not only play important role in non-small cell lung cancer, they are also found be critical in for many other diseases such as inincluding patients with ALCL patients, colorectal cancer (Lin et al., 2009; Lipson et al., 2012), IMT (Lawrence et al., 2000); ovarian cancer (Ren et al., 2012) diseases. ALK gene amplification and activating mutants were also reported in glioblastoma (Chen et al., 2008; George et al., 2008; Janoueix-Lerosey et al., 2008; Mosse et al., 2008). Different ALK fusion forms were found for different diseases. For example, the most frequently observed form is EML4-ALK in non-small cell lung cancer and the most frequently found form is NPM-ALK in ALCL. Furthermore, ALK gene amplification and mutation were also reported in glioblastma. Some of these ALK mutations are also sensitive to ALK inhibitors, and potentially benefit from ALK inhibitor development.

Although there are great benefit for patients of using ALK kinase inhibitors in clinic, drug resistance eventually developed usually about one year after drug treatment initiation. Part of the reason is because ALK gene amplification or acquired resistance mutation in ALK protein, including L1196M, L1198F, L1152R, L1151TIN, C1156Y, F1174C, G1202R, D1203N, S1206Y (Bordi et al., 2017; Dagogo-Jack and Shaw, 2016; Drizou et al., 2017). The most frequent mutation is the Point mutation L1196M which was called gatekeeper mutation. Because Crizotinib is hard to reach the brain, resistance was also developed after the occurrence of brain metasis. Other resistance mechanisms are activation of other driver genes, including EGFR mutation or activation (30-35%), c-KIT amplification (10%) or Kras or other gene mutations (5%) (Bordi et al., 2017).

Studies on drug resistance mechanisms impeded the development of the second generation of ALK kinase inhibitor drugs, which include Ceritinib (Novartis, LDK378), Alectinib (Roche, CH542802) and Brigtinib (Ariad, AP26113). These drugs can overcome many acquired resistance mutations in ALK, including gatekeeper mutation L1196M. In addition, these drugs can penetrate into the brain very well and inhibit the growth of brain metasized tumor. Within these drugs, certinib was approved by FDA in 2014 to treat patients progressed on Crizotinib treatment or patients who are not Crizotinib-tolerated. Second line treatment with Ceritinib increased progression free survival for about 4 months comparing to second line chemotherapy (Shaw et al., 2017). Alectinib was approved in 2014 in Japan and 2015 by FDA in US. It is about 10 fold more potent than Crizotinib in inhibiting ALK kinase activities. The advantage of second line using Alectinib over chemotherapy after Crizotinib resistance was recently reported (Asao et al., 2017). It increased the patients' progression free survival up to 35 months. This indicated that of using ALK kinase inhibitor drugs with optimized drug treatment strategies might make the uncontrolled tumor growth to a controllable chronic diseases. Brigatinib (Takeda) was firstly approved by FDA as breakthrough designation on Apr. 28, 2017 for second line treatment ALK-positive patients who developed resistance to Crizotinib. Comparing to two other 2nd generation drugs, Brigatinib not only effectively inhibited G1269A, C1156Y, I1171S/T, V1180L, it also blocked the resistance mediated by G1202R (Zhang et al., 2016). In addition, Brigatinib can blocked the activities of both ALK and EGFR, the response rate is 55% and disease control rate was about 86%. Currently, it has been granted priority review as a first-line treatment for ALK positive non-small cell lung cancer.

Although the development of new generation specific tyrosine kinase inhibitor drugs showed high response rate in ALK mutant positive non-small cell lung cancer, drug resistance still occurrs. The 3^(rd) generation ALK kinase inhibitor Lorlatinib (PF-06463922) can overcome many known acquired ALK mutations, patients who developed resistance to Lortinib eventually occurred. The number of patients with ALK rearrangement mutation is big and it contuse rising. Drug resistance to target therapy become a big obstacle to improve patients survival and the development need of the society. The need for overcome drug resistance is big and development new types of drugs to overcome resistance is urgent.

Proteolysis targeting technology is a new strategy of drug design. Traditional small molecular design only inhibit the kinase activity of ALK protein, whereas the acquired resistance mutation on the protein is the basis of certain resistance mechanism. We utilize the platform of Proteolysis targeting drug (PROTAD) to develop new ALK targeting drugs. The action mechanisms of these drugs is distinct from traditional small kinase inhibitors. These PROTAD drugs not only inhibit the activity of target proteins such as ALK, but also are able to get rid of target proteins through proteolysis. By using the PROTAC technology, we would like to develop new drugs targeting cancer driver genes such as ALK fusion proteins and getting rid of these target proteins ultimately so as to treat cancer and overcome drug resistance.

SUMMARY OF THE INVENTION

The present disclosure provides a compound of formula (I):

or its salts, enantiomers, stereoisomers, solvates, or polymorphs, wherein all substituents or groups are as defined in the detailed description of the invention.

The present disclosure also provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The present disclosure also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament:

wherein all substituents or groups are as defined in the detailed description of the invention.

The present disclosure also provides the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of cancer, especially lung cancer.

The present disclosure further provides the use of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing and/or treating cancer.

The Cancers include, but are not limited to, lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, Ros1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer; Lymphoma including anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), and diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor including glioma, and glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.

The present disclosure also provides a method for treating or preventing cancer, which comprises administering to a subject a therapeutically effective amount of said compound of formula (I), or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition according to the present disclosure.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows ALK protein degradation activities for Brigatinib Analogue A-based PROTAD molecules according to the present invention in ALCL cell line SR;

FIG. 2 shows ALK protein degradation activities for Brigatinib Analogue A-based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 3 shows ALK protein degradation activities for Brigatinib Analogue B-based PROTAD molecules according to the present invention in ALCL cell line SR;

FIG. 4 shows ALK phosphorylation and protein degradation activities for Brigatinib Analogue B-based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 5 shows ALK phoshorylation, protein degradation activities and inhibition of downstream signaling pathway for Brigatinib Analogue B-based PROTAD molecules according to the present invention in lung cancer cell line H2228;

FIG. 6 shows ALK protein degradation activities for Brigatinib Analogue C-based PROTAD molecules according to the present invention in ALCL cell line SR;

FIG. 7 shows ALK phosphorylation and protein degradation activities for Brigatinib Analogue C-based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 8 shows ALK phoshorylation and protein degradation activities for Brigatinib Analogue C-based PROTAD molecules according to the present invention in lung cancer cell line H2228;

FIG. 9 shows ALK protein degradation activities for Alectinib Analogue A-based PROTAD molecules according to the present invention in ALCL cell line SR;

FIG. 10 shows ALK phosphorylation, protein degradation activities and downstream signaling pathway for Alectinib Analogue A-based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 11 shows ALK protein degradation activities for Ceritinib based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 12 shows ALK phosphorylation, protein degradation activities and downstream signaling pathway for Crizotinib based PROTAD molecules according to the present invention in lung cancer cell line H3122;

FIG. 13 shows that PROTAD molecules according to the present invention reduced ALK protein stability;

FIG. 14 shows time-dependent and concentration dependent effect of Brigatinib on ALK protein in SR cell lines;

FIG. 15 shows that Brigatini-based PROTAD molecules according to the present invention degrade ALK protein in SR cell lines in the manner of time-dependent way;

FIG. 16 shows that the PROTAD molecules according to the present invention act through proteosome-mediated proteolysis pathway (SR cell line);

FIG. 17 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines H2228;

FIG. 18 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines PC9;

FIG. 19 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines PC9Brc1;

FIG. 20 shows the effect of PROTAD molecules according to the present invention on cell growth in colorectal cancer cell lines SW48.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present disclosure are very effective in degrading ALK tyrosine kinases associated with lung cancer in the cellular environment. These compounds of the present disclosure are based on PROteolytic TArgeted Chimeras (PROTAC) technology, in which one end of the compound is bound to VHL or CRBN protease with ubiquitination function, and the other end is bound to a targeted tyrosine kinase. When the compound of the present disclosure is combined with a tyrosine kinase and VHL or CRBN protease, a complex is formed, so that VHL or CRBN protease is in close proximity to the tyrosine kinase, resulting in the ubiquitination of the tyrosine kinase and its subsequent proteasome degradation.

Accordingly, in a first aspect the present disclosure provides a compound of formula (I):

-   or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof,     in which: -   ALK-TKI is covalently connected to LIN via group A, and ULM is     covalently connected to LIN; wherein ALK-TKI is an ALK tyrosine     kinase inhibitor or an analogue thereof with the same function; -   LIN is a linking group, which represents a linear or branched     alkylene chain, a spiro-cycloalkylene, a 1,4-piperazinylene, or a     1,3-dialkynyl group, wherein the linear or branched alkylene chain     is optionally interrupted one or more times (e.g., 1-20, 1-15, 1-10,     1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 times, or 1 time) by one     or more selected from the group consisting of O, C(O)NH, NHC(O),     NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene,     alkenylene, cycloalkylene, arylene, heterocyclylene, or     heteroarylene group, or any combination thereof, wherein the linear     or branched alkylene chain is optionally substituted with one or     more substituents (e.g., as described herein);     -   ULM is a small molecule ligand of VHL or CRBN protease with         ubiquitination function; and -   the group A is C(O) or absent.

In the present disclosure, the term “alkylene” (which is used interchangeably with “alkylene chain”) used alone or in combination refers to a linear or branched chain divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term “C_(x)-C_(y) alkylene” or “C_(x-y) alkylene” (x and y are each an integer) as used herein refers to a linear or branched alkylene group containing from x to y carbon atoms. In another embodiment, an “alkylene” radical includes, but are not limited to, C₁-C₃₀ alkylene group (i.e., C₁₋₃₀ alkylene group), or C₁-C₂₉ alkylene, C₁-C₂₈ alkylene, C₁-C₂₇ alkylene, C₁-C₂₆ alkylene, C₁-C₂₅ alkylene, C₁-C₂₄ alkylene, C₁-C₂₃ alkylene, C₁-C₂₂ alkylene, C₁-C₂₁ alkylene, C₁-C₂₀ alkylene, C₁-C₁₉ alkylene, C₁-C₈ alkylene, C₁-C₁₇ alkylene, C₁-C₁₆ alkylene, C₁-C₁₅ alkylene, C₁-C₁₄ alkylene, C₁-C₁₃ alkylene, C₁-C₁₂ alkylene, C₁-C₁₁ alkylene, C₁-C₁₀ alkylene, C₁-C₉ alkylene, C₁-C₈ alkylene, C₁-C₇ alkylene, C₁-C₆ alkylene, C₁-C₅ alkylene, C₁-C₄ alkylene, C₁-C₃ alkylene, or C₁-C₂ alkylene. Representative examples of “alkylene” group include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene.

In the present disclosure, the term “arylene” used alone or in combination refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene group, naphthylene group or fluorenylene group. In the present disclosure, the “arylene” is an optionally substituted arylene. A substituted arylene group refers to an arylene group optionally substituted 1-3 times with a substituent(s) (that is, the arylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “aryl” used alone or in combination refers to a monovalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the “aryl” is an optionally substituted aryl. A substituted aryl refers to an aryl group optionally substituted 1-3 times with a substituent(s) (that is, the aryl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “C₁₋₃alkoxy group” used alone or in combination refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C₁₋₃alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. In a further embodiment, examples of C₁₋₃alkoxy are methoxy and ethoxy.

In the present disclosure, the term “cycloalkyl” used alone or in combination refers to a saturated or partially unsaturated (e.g., containing one or more double bonds but not having a completely conjugated it-electron system) monovalent monocyclic or bicyclic cyclic hydrocarbon radical, which may include fused, bridged, or spiro ring system, having from 3 to 12 carbon atoms, e.g., having from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms. Representative examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, and spiro-cycloalkyl.

In the present disclosure, the cycloalkyl group may be unsubstituted or substituted. A substituted cycloalkyl group refers to a cycloalkyl group optionally substituted 1-3 times by a substituent(s) (that is, the cycloalkyl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “cycloalkylene”, used alone or in combination, refers to a saturated and partially unsaturated (e.g., containing one or more double bonds, but not having a fully conjugated π-electron system) divalent monocyclic or bicyclic cyclic hydrocarbon group, which may include fused, bridged, or spiro ring system, having from 3 to 12 carbon atoms, e.g., having from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms. Representative examples of “cycloalkylene” include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, and spiro-cycloalkylene.

In the present disclosure, the cycloalkylene group may be unsubstituted or substituted. A substituted cycloalkylene group refers to a cycloalkylene group optionally substituted 1-3 times by a substituent(s) (that is, the cycloalkylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “heteroarylene” used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group containing one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridinylene, 1H-pyrrolo[3,2-b]pyridinylene, 1H-pyrrolo[2,3-b]pyridinylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. In the present disclosure, the heteroarylene group may be unsubstituted or substituted. A substituted heteroarylene group refers to a heteroarylene group optionally substituted 1-3 times by a substituent(s) (that is, the heteroarylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “heteroaryl” used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic monovalent aromatic ring containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 4H-fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. In the present disclosure, the heteroaryl groups may be unsubstituted or substituted. A substituted heteroaryl group refers to a heteroaryl group optionally substituted 1-3 times with a substituent(s) (that is, the heteroaryl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “heterocyclylene” used alone or in combination refers to a 4- to 6-membered saturated monocyclic divalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 4, or from 1 to 3, or from 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclylene group include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, triazolylend, tetrahydrofuranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, and dioxanylene. In the present disclosure, the heterocyclylene group may be unsubstituted or substituted as explicitly defined. A substituted heterocycloalkylene refers to a heterocycloalkylene group optionally substituted 1-3 times by a substituent(s) (that is, the heterocycloalkylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

In the present disclosure, the term “heterocyclyl” used alone or in combination refers to a 4-to 6-membered saturated monocyclic monovalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 4, or from 1 to 3, or from 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclyl group include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxanyl. In the present disclosure, the heterocyclyl may be unsubstituted or substituted as explicitly defined. A substituted heterocyclyl group refers to a heterocyclyl group optionally substituted 1-3 times with a substituent(s) (that is, the heterocycloalkylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent may be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxy, or any combination thereof.

In the present disclosure, the term “spiro-cycloalkylene” used alone or in combination refers to a divalent alicyclic hydrocarbon group derived by removing two hydrogen atoms from any one or two free valence carbon atom(s) of the alicyclic hydrocarbon group in which two rings share one common carbon atom. Representative examples of spiro-cycloalkylene group include, but are not limited to, spiro[3.3]heptanylene (for example

spiro[4.5]decanylene, spiro[5.5]undecanylene, 4-methylspiro[2.4]heptanylene etc. In the present disclosure, the term “spiro-cycloalkyl” used alone or in combination refers to a monovalent alicyclic hydrocarbon group derived by removing one hydrogen atom from a free valence carbon atom of the alicyclic hydrocarbon group in which two rings share one common atom. Representative examples of spiro-cycloalkyl group include, but are not limited to, spiro[3.3]heptanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, 4-methylspiro[2.4]heptanyl etc.

In the present disclosure, the term “alkynylene” used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkynylene group include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

In the present disclosure, the term “alkynyl” used alone or in combination refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-dialkynyl.

In the present disclosure, the term “alkenylene” used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkenylene group include, but are not limited to, vinylidene (e.g., —CH═CH—), 1-propenylene, and 1-butenylene.

In the present disclosure, the term “alkenyl” used alone or in combination refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkenyl group include, but are not limited to, vinyl, 1-propenyl, and 1-butenyl.

In the present disclosure, the term “halogen atom” or “halogen” used alone or in combination refers to fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.

In the present disclosure, the term “alkyl” used alone or in combination refers to a linear or branched alkyl group. The term “(C_(x)-C_(y)) alkyl” or “C_(x-y) alkyl” (x and y are each an integer) as used herein refers to a linear or branched chain alkyl group containing from x to y carbon atoms.

The term “C₁₋₁₀ alkyl” used alone or in combination in the present disclosure refers to a linear or branched chain alkyl group containing from 1 to 10 carbon atoms. The C₁₋₁₀ alkyl group of the present disclosure includes, but are not limited to, a C₁₋₉ alkyl group, or a C₁₋₈ alkyl group, or a C₂₋₈ alkyl group, or a C₁₋₇ alkyl group, or a C₁₋₆ alkyl, C₁₋₅ alkyl, or C₁₋₄ alkyl. Representative examples of the alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term “C₁₋₃ alkyl group” in the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms, and its representative examples include methyl, ethyl, n-propyl, and isopropyl.

In the present disclosure, the “alkyl” is optionally substituted, and the substituent(s) can be one or more selected from the group consisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, heterocyclyl, or any combination thereof.

In one embodiment of the present disclosure, the ALK-TKI represents the compound moiety represented by the following general formula:

wherein, R represents an alkyl group or H. In a sub-embodiment of the present disclosure, R represents a linear or branched C₁₋₁₀ alkyl group. In a further sub-embodiment of the present disclosure, the C₁₋₁₀ alkyl group is preferably a C₁₋₉ alkyl group, more preferably a C₁₋₈ alkyl group, still more preferably a C₂₋₈ alkyl group, and more preferably a C₁₋₇ alkyl group, even more preferably C₁₋₆ alkyl, C₁₋₅ alkyl, or C₁₋₄ alkyl. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and tert-pentyl.

In one embodiment of the present disclosure, the ULM represents a structure represented by the following formula (II):

wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group (i.e., C(O)) or is absent.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents N—, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of the formula (II), X represents C(O), Y represents NH, and Z represents a carbonyl group.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents NH, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents NH, and Z represents a carbonyl group.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents O, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents O, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of the formula (II), X represents C(O), Y represents O, and Z represents a carbonyl group.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents O, and Z represents a carbonyl group.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents CH₂, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents CH₂, and Z represents a carbonyl group.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents CH₂, and Z is absent.

In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents CH₂, and Z represents a carbonyl group.

In one embodiment of the present disclosure, the ULM represents a structure represented by the following formula (III):

wherein Z represents a carbonyl group or is absent.

In one embodiment of the present disclosure, the LIN represents: a linear or branched C₁-C₂₀ alkylene chain; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)—; —(CR₁R₂)_(n1)—(O(CR₁R₂)_(n2))_(m1)—O—(CR₁R₂)_(n3)—; —(CH₂)_(n1)—(C(O)NH—(CH₂)_(n2))_(m1)—; —(CH₂)_(n1)—(C(O)NH—(CH₂)_(n2))_(m1)—(CH₂)_(n3)—; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)—C(O)NH—(CH₂)_(n4)—(O(CH₂)_(n5))_(m2)—O—(CH₂)_(n6)—; —(CR₁R₂)_(n1)—(O(CR₁R₂)_(n2))_(m1)—O—(CR₁R₂)_(n3)—C(O)NH—(CR₁R₂)_(n4)—(O(CR₁R₂)_(n5))_(m2)—O—(CR₁R₂)_(n6)—; (CH₂)_(n1)—C(O)NH—(O(CR₁R₂)_(n2))_(m1)—; a linear or branched alkylene chain interrupted one or more times (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 times, or 1 time) by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene, or any combination thereof; or —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)— in which carbon chain is interrupted one or more times (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 times, or 1 time) by one or more selected from the group consisting of arylene, heterocyclylene, heteroarylene group or any combination thereof;

wherein R₁ and R₂ each independently represent a linear or branched C₁-C₁₀ alkyl group or a cycloalkyl group; and

n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Herein, when LIN represents a linear or branched alkylene chain which is optionally substituted and optionally interrupted one or more times by one or more selected from the group consisting of O, C(O)NH, NHC(O), NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene group, or any combination thereof, as described herein, any one of the two ends of the backbone chain of the alkylene group can be bonded to the group A, and the other end is bonded to the ULM moiety, and vice versa.

In an embodiment of the present disclosure, the LIN represents:

—(CH₂)₂O(CH₂)₂OCH₂—; —CH₂O(CH₂)₂OCH₂—; —(CH₂)₃O(CH₂)₂—;

—(CH₂)₃O(CH₂)₂O(CH₂)₂—; —(CH₂)₃O(CH₂)₃—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂—;

—(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃—;

—(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—;

—(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—;

—(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; or

—(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃—.

In an embodiment of the present disclosure, the LIN represents: —CH₂—; —(CH₂)₂—; —(CH₂)₃—; —(CH₂)₄—; —(CH₂)₅—; —(CH₂)₆—; —(CH₂)₇—; —(CH₂)₈—; —(CH₂)₉—; —(CH₂)₁₀—; —(CH₂)₁₁—; —(CH₂)₁₂—; —(CH₂)₁₃—; —(CH₂)₁₄—; —(CH₂)₁₅—; —(CH₂)₁₆—; —(CH₂)₁₇—; —(CH₂)₁₈—; —(CH₂)₁₉—; or —(CH₂)₂₀—.

In one embodiment of the present disclosure, the linear or branched alkylene chain is substituted one or more times (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 times, or 1 time) with one or more substituents, wherein the substituents are selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof.

In one embodiment of the present disclosure, the LIN represents a linear or branched C₁-C₂₀ alkylene chain substituted with one or more substituents selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof. In a sub-embodiment of the present disclosure, the number of the substituent may be, for example, 1-20, or 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1.

In one embodiment of the present disclosure, the LIN represents-(CH₂)₃CH(OH)CH(OH)(CH₂)₄—.

In an embodiment of the present disclosure, the LIN represents: —(CH₂)_(n1)-triazolylene-(CH₂)_(n2)—; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)-triazolylene-(CH₂)_(n4)—(O(CH₂)_(n5))_(m2)—O—(CH₂)_(n6); —(CH₂)_(n1)-triazolylene-(CH₂)_(n2)—(O(CH₂)_(n3))_(m1)—O—(CH₂)_(n4)—; or —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)- triazolylene-(CH₂)_(n4)—; and

n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In an embodiment of the present disclosure, the LIN represents:

In an embodiment of the present disclosure, the LIN represents: —(CH₂)₂C(O)NH(CH₂)₂—; —(CH₂)₃C(O)NH(CH₂)₃—; —(CH₂)₃C(O)NH(CH₂)₄—; —(CH₂)₆C(O)NH(CH₂)₇—; or —(CH₂)₈C(O)NH(CH₂)₈—.

In one embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—NHC(O)—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN is —(CH₂)₃NHC(O)(CH₂)₃—.

In an embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—NHC(O)NH—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN is —(CH₂)₄NHC(O)NH(CH₂)₄—.

In an embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—S—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents: —(CH₂)₅S(CH₂)₅— or —(CH₂)₆S(CH₂)₅—.

In an embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—S(O)—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents: —(CH₂)₅S(O)(CH₂)₅— or —(CH₂)₆S(O)(CH₂)₅—.

In one embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—S(O)₂—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents: —(CH₂)₅S(O)₂(CH₂)₅— or —(CH₂)₆S(O)₂(CH₂)₅—.

In an embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—CH═CH—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN is —(CH₂)₄CH═CH(CH₂)₃—.

In one embodiment of the present disclosure, the LIN is —(CH₂)_(n1)—C≡C—(CH₂)_(n2)— or —(CH₂)_(n1)—C≡C—C≡C—(CH₂)_(n2)—, wherein n1, n2 independently represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents —(CH₂)₂C═C(CH₂)₂— or —(CH₂)₈C═C(CH₂)₄—.

In one embodiment of the present disclosure, the LIN represents a linear or branched alkylene chains interrupted one or more times (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 times, or 1 time) by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, spiro-cycloalkylene, arylene, heterocyclylene, heteroarylene group, or any combination thereof.

In one embodiment of the present disclosure, the LIN represents —(CH₂)_(n1)-piperazinylene-(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents —CH₂-piperazinylene-CH₂—, —(CH₂)₂-piperazinylene-(CH₂)₂—, —(CH₂)₃-piperazinylene-(CH₂)₃—, —(CH₂)₂-piperazinylene-(CH₂)₃—, —CH₂-piperazinylene-(CH₂)₂—, —CH₂-piperazinylene-(CH₂)₃—, or —(CH₂)₂-piperazinylene-(CH₂)₃—.

In an embodiment of the present disclosure, the LIN represents —(CH₂)_(n1)-phenylene-(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In one embodiment of the present disclosure, the LIN represents —CH₂-phenylene-CH₂—, —(CH₂)₂-phenylene-(CH₂)₂—, —CH₂-phenylene-(CH₂)₂—, —(CH₂)₂-phenylene-CH₂-, —(CH₂)₃-phenylene-(CH₂)₃—, —CH₂-phenylene-(CH₂)₃—, —(CH₂)₂-Phenylene-(CH₂)₃—, —(CH₂)₃-phenylene-(CH₂)₂—, or —(CH₂)₃-phenylene-CH₂—.

In one embodiment of the present disclosure, the LIN represents a 1,4-piperazinylene, a spiro-cycloalkylene, or a 1,3-dialkynylene group, wherein when LIN is a 1,4-piperazinylene, the group A of the compound of formula (I) is a carbonyl group.

In one embodiment of the present disclosure, the LIN represents

wherein when the LIN is a 1,4-piperazinylene, the group A of the compound of the formula (I) is a carbonyl group.

In one embodiment of the present disclosure, the LIN represents a spiro-cycloalkylene, and the spiro-cycloalkylene may be a spiro[3.3]heptanylene (for example

spiro[4.5]decanylene, spiro[5.5]undecanylene, or 4-methylspiro[2.4]heptanylene.

In an embodiment of the present disclosure, the LIN represents:

and the group A is C(O).

Particularly preferred are the following compounds of formula I and their salts (especially pharmaceutically acceptable salts) in Tables 1 and 2 of the present disclosure:

TABLE 1 Structural formulas and names of the compounds of the present disclosure Compound ID Structure of the compound Name of the compound SIAI S119 7065

4-((2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S119 7067

4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S119 7069

4-((2-(2-(2-(3-(4-(4-((4-((2- (dimethylphosphoryl)phenyl)amino)-5- methylpyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione SIAI S119 7071

4-((15-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-15-oxo- 3,6,9,12-tetraoxapentadecyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S119 7073

4-((18-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-18-oxo- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

4-((18-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

3-(4-((2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((2-(2-(2-(3-(4-(4-((4-((2- (dimethylphosphoryl)phenyl)amino)-5- methylpyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione

3-(4-((15-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-15-oxo- 3,6,9,12-tetraoxapentadecyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((18-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-18-oxo- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione

3-(4-((18-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione

4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)propoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-(2-(2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-(19-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)- 4,7,10,13,16-pentaoxanonadecyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S119 7055

4-((2-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S119 7057

4-((3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S119 7059

4-((4-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4- oxobutyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S119 7061

4-((5-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-5- oxopentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S119 7063

4-((6-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-6- oxohexyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S119 7077

4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((2-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-2- oxoethyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-((3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-((4-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4- oxobutyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-((5-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-5- oxopentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-((6-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-6- oxohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-N-(2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)-7- oxoheptanamide

7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-N-(2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)-7-oxoheptanamide

4-((2-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)ethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((2-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)ethyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)heptyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)heptyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-N-(2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)heptanamide

4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)oxy)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)oxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

4-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

3-(4-(3-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-(8-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-8- oxooctyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

4-((5-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)thio)pentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((5-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)sulfinyl)pentyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

4-((5-((7-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptyl)sulfonyl)pentyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

4-((12-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-12- oxododec-5-yn-1-yl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((8-(4-(6-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-6- oxohexyl)-1H-1,2,3-triazol-1- yl)octyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S119 7087

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7079

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)propoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7081

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4- ((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4,16- dioxo-7,10,13-trioxa-3- azahexadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7083

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4- ((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4,19- dioxo-7,10,13,16-tetraoxa-3- azanonadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7085

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4- ((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4,22- dioxo-7,10,13,16,19-pentaoxa-3- azadocosanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7145

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4- oxobutanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S119 7147

(2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-5- oxopentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7149

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7151

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-7- oxoheptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1- yl)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7153

(2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-8- oxooctanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S119 7155

(2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-9- oxononanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S119 7157

(2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

N1-(4-(4-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperazin-1-yl)-4- oxobutyl)-N5-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)glutaramide SIAI S151 113

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2- ((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)propanamide SIAI S151 114

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanamide SIAI S151 115

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanamide SIAI S151 116

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-1-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan-15-amide SIAI S151 117

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-1-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18- amide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2- ((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)ethoxy)propanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-1-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan-15-amide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-1-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18-amide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy) propanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- (2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy) propanamide

4-((2-(2-(2-(3-((1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)propoxy)ethoxy)ethoxy)ethyl) amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

3-(4-((2-(2-(2-(3-((1-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)propoxy)ethoxy)ethoxy)ethyl) amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2-(2- (3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)propoxy)ethoxy)ethoxy)propanamide SIAI S151 120

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)acetamide SIAI S151 121

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propanamide SIAI S151 118

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-4-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butanamide SIAI S151 119

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-5-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentanamide SIAI S151 122

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-6-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)hexanamide SIAI S151 123

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-7-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)heptanamide SIAI S219 151

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-2-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)acetamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)propanamide SIAI S219 128

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-4-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)butanamide SIAI S219 152

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-5-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)pentanamide SIAI S219 153

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-6-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)hexanamide SIAI S219 154

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-7-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)heptanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-7-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)heptanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-7-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)heptanamide SIAI S220 330

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-4-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)-N- methylbutanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-4-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)-N- methylbutanamide SIAI S220 026

4-((4-((1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)butyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((4-((1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)butyl)amino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione

4-((4-((1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)(methyl)amino)butyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((7-((1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)heptyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S219 170

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)propanamide

N-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-3-(2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)propanamide

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N7-(2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)heptanediamide SIAI S151 128

(2S,4R)-1-((S)-2-(2-(2-(2-((1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 2-oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 124

(2S,4R)-1-((S)-2-(3-(2-(3-((1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 3-oxopropoxy)ethoxy)propanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S151 125

(2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4- ((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 4,16-dioxo-7,10,13-trioxa-3- azaliexadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 126

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N16- ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)- 4,7,10,13-tetraoxahexadecanediamide SIAI S151 127

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N19- ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)- 4,7,10,13,16- pentaoxanonadecanediamide SIAI S164 143

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N4-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)succinamide SIAI S164 144

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N5-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)glutaramide SIAI S164 145

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N6-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)adipamide SIAI S164 146

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N7-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)heptanediamide SIAI S164 147

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N8-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)octanediamide SIAI S164 148

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N9-((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)nonanediamide SIAI S164 149

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N10- ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)decanediamide SIAI S121 0117

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N11- ((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)undecanediamide

(2S,4R)-1-((S)-2-(8-((1-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-((8-((1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)octyl)amino)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(11-((1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 11-oxoundecyl)amino)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)amino)undecyl)amino)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 3-oxopropyl)piperazin-1- yl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)amino)- 3-oxopropyl)phenyl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 157

N1-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)-N4-(2- ((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethyl)succinamide SIAI S164 007

4-((2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S164 008

4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 009

4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione SIAI S164 016

4-((15-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-15-oxo-3,6,9,12- tetraoxapentadecyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S164 017

4-((18-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-l-yl)-18-oxo-3,6,9,12,15- pentaoxaoctadecyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4- ((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione

3-(4-((15-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-15-oxo-3,6,9,12- tetraoxapentadecyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((18-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-18-oxo-3,6,9,12,15- pentaoxaoctadecyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1- yl)propoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1- yl)propoxy)ethoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1- yl)propoxy)ethoxy)propyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1- yl)propoxy)ethoxy)propyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

4-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S164 018

4-((2-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-2-oxoethyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 019

4-((3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3-oxopropyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 020

4-((4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 021

4-((5-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-5-oxopentyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 022

4-((6-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-6-oxohexyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 023

4-((7-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-7-oxoheptyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S164 073

3-(4-((2-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-2-oxoethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3-oxopropyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione SIAI S219 155

3-(4-((4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S219 156

3-(4-((5-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-5-oxopentyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione SIAI S219 157

3-(4-((6-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-6-oxohexyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione SIAI S219 124

3-(4-((7-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-7-oxoheptyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione SIAI S219 158

4-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3-oxopropyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3-oxopropyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

4-(4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

4-(5-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-5-oxopentyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)butyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S220 027

4-((2-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((2-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S164 041

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 032

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1- yl)propoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 033

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1- (4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4,16-dioxo-7,10,13- trioxa-3-azahexadecanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 034

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1- (4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4,19-dioxo- 7,10,13,16-tetraoxa-3- azanonadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 035

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1- (4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4,22-dioxo- 7,10,13,16,19-pentaoxa-3- azadocosanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 120

(2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 121

(2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-5-oxopentanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 122

(2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-6-oxohexanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 123

(2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-7-oxoheptanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 124

(2S,4R)-1-((S)-2-(8-(4-(-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-8-oxooctanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 125

(2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro- 4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-9-oxononanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 126

(2S,4R)-1-((S)-2-(10-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-10-oxodecanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 152

4-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-N-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethyl)-4- oxobutanamide SIAI S164 153

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-4-oxobutyl)-1H- 1,2,3-triazol-1-yl)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropyl)piperazin-1- yl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5- chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropyl)phenyl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

3-(4-((2-(4-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropyl)piperazin-1-yl)ethyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione

3-(4-((4-(3-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4- yl)piperazin-1-yl)-3- oxopropyl)phenethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S164 011

8-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperazin- 1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 012

8-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl) piperazin-1-yl)-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S164 013

8-(4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanoyl)piperazin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S164 014

8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan-15- oyl)piperazin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S164 015

8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18- oyl)piperazin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperazin- 1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propyl)piperazin-1- yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 028

8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)glycyl)piperazin- 1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 029

8-(4-(3-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)propanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 024

8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)butanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 025

8-(4-(5-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 026

8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)hexanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 030

8-(4-(7-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)heptanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)glycyl)piperazin-1- yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)hexanoyl)piperazin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S164 040

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 036

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 037

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-4,16-dioxo-7,10,13- trioxa-3-azahexadecanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 038

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-4,19-dioxo- 7,10,13,16-tetraoxa-3- azanonadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 039

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-4,22-dioxo- 7,10,13,16,19-pentaoxa-3- azadocosanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S164 093

(2S,4R)-1-((S)-2-(4-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-4-oxobutanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 094

(2S,4R)-1-((S)-2-(5-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-5-oxopentanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 095

(2S,4R)-1-((S)-2-(6-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-6-oxohexanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 096

(2S,4R)-1-((S)-2-(7-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-7-oxoheptanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 097

(2S,4R)-1-((S)-2-(8-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-8-oxooctanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 098

(2S,4R)-1-((S)-2-(9-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-9-oxononanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 099

(2S,4R)-1-((S)-2-(10-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-10-oxodecanamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S164 154

4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperazin-1-yl)-N-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethyl)-4- oxobutanamide SIAI S164 155

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)-4-oxobutyl)-1H- 1,2,3-triazol-1-yl)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(8-(4-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperazin-1-yl)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-3-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)propanamide SIAI S219 023

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanamide SIAI S219 024

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan-15-amide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18- amide SIAI S219 001

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)acetamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-3-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propanamide SIAI S219 010

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butanamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-5-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentanamide SIAI S219 011

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-6-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)hexanamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-2-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)acetamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butanamide

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H-benzo[b]carbazol- 8-yl)piperidin-4-yl)-6-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)hexanamide

(2S,4R)-1-((S)-2-(2-(2-(2-((1-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)amino)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-((1-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)amino)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)amino)-4,16-dioxo- 7,10,13-trioxa-3-azahexadecanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N16-((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)- 4,7,10,13-tetraoxahexadecanediamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N19-((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)- 4,7,10,13,16- pentaoxanonadecanediamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)succinamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)glutaramide SIAI S219 020

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)adipamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)heptanediamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)octanediamide

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)nonanediamide SIAI S219 021

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazol-8-yl)piperidin-4-yl)- N10-((S)-1-((2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)decanediamide

(2S,4R)-1-((S)-2-(4-(4-(4-((1-(3-cyano- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)amino)-4-oxobutyl)- 1H-1,2,3-triazol-1-yl)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

8-(4-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperazin- 1-yl)piperidin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S219 018

8-(4-(4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl) piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy) propanoyl)piperazin-1-yl)piperidin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile SIAI S219 019

8-(4-(4-(1-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan-15- oyl)piperazin-1-yl)piperidin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(4-(1-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18- oyl)piperazin-1-yl)piperidin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl) piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)propanoyl) piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S184 194

8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)glycyl)piperazin-1-yl)piperidin-1-yl)- 9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(4-(3-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)propanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S219 003

8-(4-(4-(4-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)butanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(5-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile SIAI S219 004

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)hexanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(7-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)heptanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)heptanoyl)piperazin-1-yl)piperidin-1- yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)oxy)hexanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4- yl)amino)hexanoyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

8-(4-(4-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)piperidin- 1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazole-3- carbonitrile

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4- yl)amino)hexyl)piperazin-1- yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1- (3-cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-4,16- dioxo-7,10,13-trioxa-3- azahexadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1- (3-cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-4,19- dioxo-7,10,13,16-tetraoxa-3- azanonadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1- (3-cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-4,22- dioxo-7,10,13,16,19-pentaoxa-3- azadocosanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(4-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-4- oxobutanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(5-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-5- oxopentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S219 015

(2S,4R)-1-((S)-2-(6-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(7-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-7- oxoheptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(8-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-8- oxooctanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(9-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-9- oxononanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S219 016

(2S,4R)-1-((S)-2-(10-(4-(1-(3-cyano-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(3- cyano-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol-8- yl)piperidin-4-yl)piperazin-1-yl)-4- oxobutyl)-1H-1,2,3-triazol-1- yl)butanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S151 031

4-((2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S151 023

4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1- yl)propoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-(2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-(3-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)propyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1- yl)propoxy)ethoxy)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione SIAI S151 028

4-((2-(2-(2-(3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione SIAI S151 029

4-((18-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-18-oxo- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S151 037

4-((2-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S151 034

4-((3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-(4-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4- oxobutyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1- yl)propyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((3-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione SIAI S151 035

4-((4-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4- oxobutyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S151 036

4-((5-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-5- oxopentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S151 043

4-((6-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-6- oxohexyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

4-((6-(4-(4-((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-6- oxohexyl)oxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione SIAI S151 042

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5- chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5- chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1- yl)ethoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 038

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5- chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 039

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4- ((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4,16- dioxo-7,10,13-trioxa-3- azahexadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 040

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4- ((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4,19- dioxo-7,10,13,16-tetraoxa-3- azanonadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 041

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4- ((5-chloro-4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4,22- dioxo-7,10,13,16,19-pentaoxa-3- azadocosanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidine-1- carbonyl)spiro[3.3]heptane-2- carboxamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S074 017

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4- oxobutanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1- yl)butanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-((4-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-4- oxobutyl)amino)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 018

(2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-5- oxopentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 021

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 022

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-7- oxoheptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 008

(2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-8- oxooctanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide SIAI S074 024

(2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4- ((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-9- oxononanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 025

(2S,4R)-l-((S)-2-(10-(4-(4-((5-chloro- 4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S074 026

(2S,4R)-1-((S)-2-(11-(4-(4-((5-chloro- 4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-11- oxoundecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(5-(5-(4-(4-((5-chloro- 4-((2- (isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-5- oxopentanamido)pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide SIAI S151 049

4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)propoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

3-(4-((2-(3-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)propoxy)ethyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-(3-(3-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)propoxy)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione SIAI S151 050

4-((2-(2-(3-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S151 051

4-((2-(2-(2-(3-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione SIAI S151 060

4-((15-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-15-oxo- 3,6,9,12-tetraoxapentadecyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S151 061

4-((18-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-18-oxo- 3,6,9,12,15-pentaoxaoctadecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione SIAI S151 083

4-((2-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S151 084

4-((3-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S151 081

4-((4-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-4- oxobutyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione SIAI S151 082

4-((5-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-5- oxopentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione SIAI S151 085

4-((6-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-8- oxooctyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-8- oxooctyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

3-(4-(9-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-9- oxononyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

4-(9-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-9- oxononyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-8- oxooctyl)oxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)-8-oxooctanamide

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)octyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fIuorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)octyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

4-((12-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-12- oxododecyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((16-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-16- oxohexadecyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

8-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-N-(7-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)heptyl)-8- oxooctanamide

4-((5-(4-(6-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexyl)-1H-1,2,3-triazol-1- yl)pentyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexyl)thio)pentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexyl)sulfinyl)pentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexyl)sulfonyl)pentyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

1-(5-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-5- oxopentyl)-3-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butyl)urea

4-(((E)-10-(4-(4-(6-amino-5-((R)-1- (2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-10-oxodec- 4-en-1-yl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

4-((10-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-5,6- dihydroxy-10-oxodecyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

4-((7-(4-(4-(6-amino-5-((R)-1-(2,6- dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-7-oxohept- 3-yn-1-yl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3- dione

(2S,4R)-1-((S)-2-(4-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-4- oxobutanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(6-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-8- oxooctanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-8- oxooctyl)amino)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)octanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)octyl)amino)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(10-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(4-(5-(4-(4-(6-amino- 5-((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-5- oxopentanamido)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6- amino-5-((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6- amino-5-((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1- yl)propoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-16-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-2-(tert- butyl)-4,16-dioxo-7,10,13-trioxa-3- azahexadecanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-19-(4-(4-(6-amino-5- ((R)-1-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3-yl)-1H- pyrazol-1-yl)piperidin-1-yl)-2-(tert- butyl)-4,19-dioxo-7,10,13,16-tetraoxa- 3-azanonadecanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

TABLE 2 Structural formulas and names of the compounds of the present disclosure Structure of the compound Name of the compound

4-((2-(3-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)- piperidin-4-yl)piperazin- 1-yl)-3-oxopropoxy)- ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)- isoindoline-1,3-dione

4-((2-(2-(3-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)- piperidin-4-yl)piperazin- 1-yl)-3-oxopropoxy)- ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((2-(2-(2-(3-(4-(1- (4-((5-chloro-4-((2- (isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-3-oxo- propoxy)ethoxy)- ethoxy)ethyl)amino)-2- (2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((18-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-18-oxo-3,6,9,12,15- pentaoxaoctadecyl)- amino)-2-(2,6-dioxo- piperidin-3-yl)isoindoline- 1,3-dione

4-((2-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1-yl)- 2-oxoethyl)amino)-2- (2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((3-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-3-oxopropyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((4-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4-oxobutyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((5-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-5-oxopentyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((6-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-6-oxohexyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((7-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-7-oxoheptyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

4-((8-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-8-oxooctyl)amino)- 2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

3-(4-((2-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-2-oxoethyl)amino)- 1-oxoisoindolin-2-yl)- piperidine-2,6-dione

3-(4-((8-(4-(2-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-8-oxooctyl)amino)- 1-oxoisoindolin-2-yl)- piperidine-2,6-dione

(2S,4R)-1-((S)-2-(2- (2-(2-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-2-oxoethoxy)ethoxy)- acetamido)-3,3-dimethyl- butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(3-(2- (3-(4-(1-(4-((5-chloro- 4-((2-(isopropylsul- fonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-3-oxopropoxy)- ethoxy)propanamido)- 3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-16-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4,16-dioxo-7,10,13- trioxa-3-azahexadeca- noyl)-4-hydroxy-N-(4- (4-methyl-thiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-19-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1-yl)- 4,19-dioxo-7,10,13,16- tetraoxa-3-azanonadeca- noyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-22-(4-(1-(4-((5- chloro-4-((2-(isopropyl- sulfonyl)phenyl)amino)- pyrimidin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin- 1-yl)-4,22-dioxo- 7,10,13,16,19-pentaoxa- 3-azadocosanoyl)-4- hydroxy-N-(4-(4-methyl- thiazol-5-yl)benzyl)- pyrrolidine-2-carbox- amide

(2S,4R)-1-((S)-2-(4- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-4-oxo- butanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(5-(4- (1-(4-((5-chloro-4-((2- (isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-5- oxopentanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(6-(4- (1-(4-((5-chloro-4-((2- (isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(6- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4- yl)piperazin-1-yl)- hexanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(7- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-7- oxoheptanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(8- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-8- oxooctanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(9- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4- yl)piperazin-1-yl)-9- oxononanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4-methyl- thiazol-5-yl)benzyl)- pyrrolidine-2-carbox- amide

(2S,4R)-1-((S)-2-(10- (4-(1-(4-((5-chloro-4- ((2-(isopropylsulfonyl)- phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

2-(2,6-dioxopiperidin- 3-yl)-4-((2-(3-(4-(1- (4-((4-((2-(isopropyl- sulfonyl)phenyl)amino)- 1,3,5-triazin-2-yl)- amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-3- oxopropoxy)ethyl)- amino)isoindoline-1,3- dione

2-(2,6-dioxopiperidin-3- yl)-4-((2-(2-(3-(4-(1- (4-((4-((2-(isopropyl- sulfonyl)phenyl)amino)- 1,3.5-triazin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1-yl)- 3-oxopropoxy)ethoxy)- ethyl)amino)isoindoline- 1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((2-(2-(2-(3-(4- (1-(4-((4-((2-(isopropyl- sulfonyl)phenyl)amino)- 1,3,5-triazin-2-yl)amino)- 3-methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-3-oxopropoxy)- ethoxy)ethoxy)ethyl)- amino)isoindoline-1,3- dione

2-(2,6-dioxopiperidin-3- yl)-4-((15-(4-(l-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-15-oxo-3,6,9,12- tetraoxapentadecyl)- amino)isoindoline-1,3- dione

2-(2,6-dioxopiperidin-3- yl)-4-((18-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-18-oxo-3,6,9,12,15- pentaoxaoctadecyl)- amino)isoindoline-1,3- dione

2-(2,6-dioxopiperidin-3- yl)-4-((2-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-2-oxoethyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((3-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-3-oxopropyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((4-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4-oxobutyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((5-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-5-oxopentyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((6-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-6-oxohexyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((7-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-7-oxoheptyl)amino)- isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3- yl)-4-((12-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-12-oxododecyl)- amino)isoindoline-1,3- dione

3-(4-((12-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-12-oxododecyl)- amino)-1-oxoisoindolin- 2-yl)piperidine-2,6- dione

N-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin- 4-yl)-12-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1-yl)- 12-oxododecanamide

3-(4-((2-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-2-oxoethyl)amino)- 1-oxoisoindolin-2-yl)- piperidine-2,6-dione

(2S,4R)-4-hydroxy-1- ((S)-2-(2-(2-(2-(4-(1- (4-((4-((2-(isopropyl- sulfonyl)phenyl)- amino)-1,3,5-triazin-2- yl)amino)-3-methoxy- phenyl)piperidin-4- yl)piperazin-1-yl)-2- oxoethoxy)ethoxy)- acetamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(3-(2-(3-(4-(1- (4-((4-((2-(isopropyl- sulfonyl)phenyl)- amino)-1,3,5-triazin-2- yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- piperazin-1-yl)-3- oxopropoxy)ethoxy)- propanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-16-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4,16-dioxo-7,10,13- trioxa-3-azahexadeca- noyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-16-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4-oxo-7,10,13- trioxa-3-azahexadeca- noyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-19-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1-yl)- 4,19-dioxo-7,10,13,16- tetraoxa-3-azanona- decanoyl)-4-hydroxy- N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-22-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-5- methoxy-2-methyl- phenyl)piperidin-4-yl)- piperazin-1-yl)-4,22- dioxo-7,10,13,16,19- pentaoxa-3-azadoco- sanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(4-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-4-oxobutanamido)- 3,3-dimethylbutanoyl)- N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(5-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-5- methoxy-2-methyl- phenyl)piperidin-4-yl)- piperazin-1-yl)-5- oxopentanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(6-(4-(1-(5- isopropoxy-4-((4-((2- (isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-2- methylphenyl)piperidin- 4-yl)piperazin-1-yl)-6- oxohexanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(7-(4-(1-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-3- methoxyphenyl)piper- idin-4-yl)piperazin-1- yl)-7-oxoheptanamido)- 3,3-dimethylbutanoyl)- N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(8-(4-(l-(4-((4- ((2-(isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-5- methoxy-2-methyl- phenyl)-piperidin-4- yl)piperazin-1-yl)-8- oxooclanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(9-(4-(1-(5- isopropoxy-4-((4-((2- (isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-2- methylphenyl)piperidin- 4-yl)piperazin-1-yl)-9- oxononanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(10-(4-(1-(5- isopropoxy-4-((4-((2- (isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-2- methylphenyl)piperidin- 4-yl)piperazin-1-yl)-10- oxodecanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-4-hydroxy-1- ((S)-2-(13-(4-(1-(5- isopropoxy-4-((4-((2- (isopropylsulfonyl)- phenyl)amino)-1,3,5- triazin-2-yl)amino)-2- methylphenyl)piperidin- 4-yl)piperazin-1-yl)-13- oxotridecanamido)-3,3- dimethylbutanoyl)-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

2-((2-((1-(N-(3-(2-((2- (2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)- propanoyl)-N-methyl- glycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(3-(2-(2-((2- (2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)- ethoxy)propanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)-13-methyl-12- oxo-3,6,9-trioxa-13- azapentadecan-15-oyl)- 5-methoxyindolin-6-yl)- amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)- 6-fluoro-N-methyl- benzamide

1-((2-(2,6-dioxopiper- idin-3-yl)-1,3-dioxoiso- indolin-4-yl)amino)-N- (2-(6-((4-((3-fluoro-2- (methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N-methyl-3,6,9,12-tetra- oxapentadecan-15-amide

1-((2-(2,6-dioxopiper- idin-3-yl)-1,3-dioxoiso- indolin-4-yl)amino)-N- (2-(6-((4-((3-fluoro-2- (methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N-methyl-3,6,9,12,15- pentaoxaoctadecan-18- amide

2-((2-((1-(N-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- glycyl)-N-methylglycyl)- 5-methoxyindolin-6- yl)amino)-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)- amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(3-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)propanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(4-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)butanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(5-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)pentanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(6-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)hexanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(7-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)heptanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(8-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)octanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

2-((2-((1-(N-(8-((2-(2,6- dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)- amino)octanoyl)-N- methylglycyl)-5-methoxy- indolin-6-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-6-fluoro-N- methylbenzamide

N1-(2-(2,6-dioxopiper- idin-3-yl)-1-oxoiso- indolin-4-yl)-N8-(2-(6- ((4-((3-fluoro-2-(methyl- carbamoyl)phenyl)amino)- 7H-pyrrolo[2,3-d]- pyrimidin-2-yl)amino)- 5-methoxyindolin-1-yl)- 2-oxoethyl)-N8-methyl- octanediamide

(2S,4R)-1-((S)-2-(tert- butyl)-14-(6-((4-((3- fluoro-2-(methyl- carbamoyl)phenyl)- amino)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)- 5-methoxyindolin-1-yl)- 12-methyl-4,11,14- trioxo-6,9-dioxa-3,12- diazatetradecanoyl)-4- hydroxy-N-(4-(4-methyl- thiazol-5-yl)benzyl)- pyrrolidine-2-carbox- amide

(2S,4R)-1-((S)-2-(tert- butyl)-16-(6-((4-((3- fluoro-2-(methyl- carbamoyl)phenyl)- amino)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)- 5-methoxyindolin-1-yl)- 14-methyl-4,13,16- trioxo-7,10-dioxa-3,14- diazahexadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-19-(6-((4-((3- fluoro-2-(methyl- carbamoyl)phenyl)- amino)-7H-pyrrolo- [2,3-d]pyrimidin-2- yl)amino)-5-methoxy- indolin-1-yl)-17-methyl- 4,16,19-trioxo-7,10,13- trioxa-3,17-diazanona- decanoyl)-4-hydroxy- N-(4-(4-methyl-thiazol- 5-yl)phenyl)pyrrolidine- 2-carboxamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N16-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyl-4,7,10,13-tetra- oxahexadecanediamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N19-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyl-4,7,10,13,16- pentaoxanonadecane- diamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N4-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methylsuccinamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N5-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methylglutaramide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N6-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyladipamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N7-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methylheptanediamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N8-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyloctanediamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N9-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methylnonanediamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N10-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyldecanediamide

N1-(2-(6-((4-((3-fluoro- 2-(methylcarbamoyl)- phenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-5-methoxy- indolin-1-yl)-2-oxoethyl)- N13-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyltridecanediamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 3-(2-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)-N- methylpropanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 3-(2-(2-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)ethoxy)- N-methylpropanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)- ethoxy)ethoxy)-N- methylpropanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 1-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- 3,6,9,12-tetraoxapenta- decan-5-amide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 1-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- 3,6,9,12,15-pentaoxa- octadecan-18-amide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)-2- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- acetamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)-3- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- propanamide

N-(1-(4-((5-chloro-4-(1H- indol-3-yl)pyrimidin-2- y])amino)-3-methoxy- phenyl)-piperidin-4-yl)- 4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- butanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 5-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- pentanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 6-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- hexanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- 7-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- heptanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)-12- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-N-methyl- dodecanamide

N-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)-12- ((2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4- yl)amino)-N-methyl- dodecanamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- N12-(2-(2,6-dioxo- piperidin-3-yl)-1-oxoiso- indolin-4-yl)-N1-methyl- dodecanediamide

(2S,4R)-1-((S)-12-(tert- butyl)-2-(1-(4-((5- chloro-4-(1H-indol-3- yl)pyrimidin-2-yl)- amino)-3-methoxy- phenyl)piperidin-4-yl)- 3,10-dioxo-5,8-dioxa- 2,11-diazatridecan-13- oyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-17-(tert- butyl)-2-(1-(4-((5- chloro-4-(1H-indol-3- yl)pyrimidin-2-yl)- amino)-3-methoxy- phenyl)piperidin-4-yl)- 3,15-dioxo-6,9,12-trioxa- 2,16-diazaoctadecan- 18-oyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- N19-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyl-4,7,10,13,16- pentaoxanonadecane- diamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- N4-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methylsuccinamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- N6-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyladipamide

(2S,4R)-1-((S)-2-(6-((1- (4-((5-chloro-4-(1H- indol-3-yl)pyrimidin-2- yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- (methyl)amino)hexan- amido)-3,3-dimethyl- butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)ammo)-3-methoxy- phenyl)piperidin-4-yl)- N8-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyloctanediamide

N1-(1-(4-((5-chloro-4- (1H-indol-3-yl)pyrimidin- 2-yl)amino)-3-methoxy- phenyl)piperidin-4-yl)- N10-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)-N1- methyldecanediamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (3-(2-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)propanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (3-(2-(2-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)ethoxy)- propanoyl)piperazin-1- yl)-2-((tetrahydro-2H- pyran-4-yl)amino)- benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)- ethoxy)propanoyl)piper- azin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)- benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)-amino)ethoxy)ethoxy)- ethoxy)propanoyl)- piperazin-1-yl)-2- ((tetrahydro-2H-pyran- 4-yl)amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4- (4-(3-(2-(2-(3-(2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- propoxy)ethoxy)ethoxy)- propanoyl)piperazin-1- yl)-2-((tetrahydro-2H- pyran-4-yl)amino)- benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4-(1- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-3,6,9,12- tetraoxapentadecan-15- oyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4- yl)amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4-(1- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18- oyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4- yl)amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- ((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)glycyl)piperazin-1- yl)-2-((tetrahydro-2H- pyran-4-yl)amino)- benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (3-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)propanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)butanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (5-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)pentanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (6-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)hexanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (7-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin- 4-yl)amino)heptanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)benzamide

N-(5-(3,5-difluorobenzyl)- 1H-indazol-3-yl)-4-(4- (12-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)dodecanoyl)- piperazin-1-yl)-2-((tetra- hydro-2H-pyran-4-yl)- amino)henzamide

(2S,4R)-1-((S)-2-(2-(2- (2-(4-(4-((5-(3,5- difluorobenzyl)-1H- indazol-3-yl)carbamoyl)- 3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)- piperazin-1-yl)-2- oxoethoxy)ethoxy)- acetamido)-3,3-dimethyl- butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-16-(4-(4-((5-(3,5- difluorobenzyl)-1H- indazol-3-yl)carbamoyl)- 3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)- piperazin-1-yl)-4,16- dioxo-7,10,13-trioxa-3- azahexadecanoyl)-4- hydroxy-N-(4-(4-methyl- thiazol-5-yl)benzyl)- pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(tert- butyl)-22-(4-(4-((5-(3,5- difluorobenzyl)-1H- indazol-3-yl)carbamoyl)- 3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)- piperazin-1-yl)-4,22- dioxo-7,10,13,16,19- pentaoxa-3-azadoco- sanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine- 2-carboxamide

(2S,4R)-1-((S)-2-(4-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)-4-oxobutanamido)- 3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(6-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)-6-oxohexanamido)- 3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(8-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)-8-oxooctanamido)- 3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(10-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)-10-oxodecanamido)- 3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methyl-thiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(13-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)-13-oxotridecan- amido)-3,3-dimethyl- butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide

(2S,4R)-1-((S)-2-(13-(4- (4-((5-(3,5-difluoro- benzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetra- hydro-2H-pyran-4-yl)- amino)phenyl)piperazin- 1-yl)tridecanamido)-3,3- dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)- benzyl)pyrrolidine-2- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(3-(2-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)propanoyl)- 3,5-dimethylpiperazine- 1-carbonyl)phenyl)- pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)ethoxy)- propanoyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)ethoxy)ethoxy)- ethoxy)propanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(1-((2-(2,6-dioxo- piperidin-3-yl)-1,3-dioxo- isoindolin-4-yl)amino)- 3,6,9,12-tetraoxapenta- decan-15-oyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(1-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)-3,6,9,12,15- pentaoxaoctadccan- 18-oyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluoro- phenyl)ethoxy)-N-(4- ((3S,5R)-4-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)glycyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluoro- phenyl)ethoxy)-N-(4- ((3S,5R)-4-(3-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)propanoyl)- 3,5-dimethylpiperazine- 1-carbonyl)phenyl)- pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(4-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)bulanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(5-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)pentanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(6-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)hexanoyl)-3,5- dimethylpiperazine-1- carbonyl)phcnyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(7-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)heptanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(10-((2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- amino)decanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(10-((2-(2,6-dioxo- piperidin-3-yl)-1-oxoiso- indolin-4-yl)amino)- decanoyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(10-((2-(2,6-dioxo- piperidin-3-yl)-1-oxoiso- indolin-4-yl)amino)- decyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(11-(2-(2,6-dioxo- piperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- undecanoyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(2-(2-(2-(((S)-1-((2S, 4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)- benzyl)carbamoyl)- pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2- yl)amino)-2-oxoethoxy)- ethoxy)acetyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-((S)-15-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidine-1- carbonyl)-16,16-dimethyl- 13-oxo-4,7,10-trioxa-14- azaheptadecanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-((S)-21-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidine- 1-carbonyl)-22,22- dimethyl-19-oxo-4,7,10,13,16-pentaoxa- 20-azatricosanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(4-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)- 4-oxobutanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluorophenyl)- ethoxy)-N-(4-((3S,5R)- 4-(6-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methyl- thiazol-5-yl)benzyl)- carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)- 6-oxohexanoyl)-3,5- dimethylpiperazine-1- carbonyl)phenyl)pyrida- zine-3-carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluoro- phenyl)ethoxy)-N-(4-((3S,5R)-4-(8-(((S)-1- ((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)- pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan- 2-yl)amino)-8-oxo- octanoyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

6-amino-5-((R)-1-(2,6- dichloro-3-fluoro- phenyl)ethoxy)-N-(4- ((3S,5R)-4-(10-(((S)-1- ((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)- pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan- 2-yl)amino)-10-oxo- decanoyl)-3,5-dimethyl- piperazine-1-carbonyl)- phenyl)pyridazine-3- carboxamide

It should be recognized that the compounds of formula (I) of the present disclosure may have a stereo configuration and can therefore exist in more than one stereoisomer form. The disclosure also relates to compounds of formula (I) having a stereo configuration in pure or substantially pure isomeric form, e.g., greater than about 90% enantiomeric/diastereomeric excess (“ee”), such as greater than about 95% ee or 97% ee, or greater than about 99% ee, and mixtures thereof, including racemic mixtures. The purification of said isomers and the separation of said isomeric mixtures may be achieved by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (for example, by using chiral intermediates) and/or chiral resolution and the like).

The present disclosure also provides a pharmaceutical composition comprising, as an active ingredient, the compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present disclosure further includes at least one additional medicine for treating or preventing cancer.

In another aspect of the present disclosure, the compound of formula (I) according to the disclosure, or a pharmaceutically acceptable salt thereof, is for use as a medicament.

In another aspect of the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, is used for preventing and/or treating cancer.

Cancers include but are not limited to lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer; Lymphoma including anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), and diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor including glioma, and glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.

In one embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, is used for preventing and/or treating lung cancer.

In one embodiment of the present disclosure, the lung cancer is e.g., selected from the group consisting of small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.

Another aspect of the present disclosure provides the use of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of cancer.

In one embodiment of the use of compound of formula (I) of the present disclosure, the cancers include but are not limited to lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer; Lymphoma including anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), and diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor including glioma, and glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.

In one embodiment, the lung cancer is e.g., selected from the group consisting of small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.

A further aspect of the present disclosure also provides a method for treating or preventing cancer, which comprises administering to a subject a therapeutically effective amount of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

In the method for treating or preventing cancer according to the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the subject by at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, Pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration.

In one embodiment of the method for treating or preventing cancer according to the present disclosure, the cancers include but are not limited to lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer; Lymphoma including anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), and diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor including glioma, and glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.

In one embodiment of the method for treating or preventing cancer according to the present disclosure, the lung cancer is e.g., selected from the group consisting of small cell lung cancer, non-small cell lung cancer (NSCLC) such as lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.

Definition

Generally, the nomenclature used herein and the laboratory procedures described below comprising those for cell culture, organic chemistry, analytical chemistry, and pharmacology and the like are those well known and commonly used in the art. Unless otherwise defined, all the scientific and technical terms used herein in combination with the present disclosure described herein have the same meaning commonly understood by those skilled in the art. In addition, the use of the word “a” or “an” when used in combination with the term “comprising” or a noun word in the claims and/or the specification may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” or “other” may mean at least a second or more.

It should be understood that whenever various aspects are described herein with term “comprising”, other similar aspects described with “consisting of” and/or “consisting essentially of” are also provided.

The term “about” used herein refers to approximately, roughly, approximately, or around. When the term “about” is used in combination with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. For example, the term “about” used herein may modify a numerical value above and below the stated value by a variance of, for example, ±20%, or ±15%, or ±10%, ±5%, or ±1%.

The term “absent” used herein in combination with a substituent(s) or group(s) means that the substituent(s) or group(s) is not present. In other words, when the substituent(s) or group(s) is not present, it becomes a bond or a bond connector. For example, in the compound of formula (I) according to the present disclosure, when the group A is absent, the ALK-TKI moiety is directly covalently bonded (or connected) to the LIN.

As used herein, the term “interrupted” of “the linear or branched alkylene chain interrupted . . . by . . . ” used alone or in combination has a definition known in the art, i.e., can refer to there is a group as defined herein (e.g., a group selected from the group consisting of O, C(O)NH, NHC(O), NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene group, or any combination thereof, as described herein) inserted between any two adjacent carbon atoms in the backbone chain of the linear or branched alkylene chain. For example, the term “the linear or branched alkylene chain interrupted one or more times by one or more “O” radicals” used alone or in combination refers to one or more pairs of any two adjacent carbon atoms in the backbone chain of the linear or branched alkylene chain are inserted therebetween with the —O— radical, to from a linear or branched oxaalkylene radical containing one or more (e.g., 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) “—CH₂—O—CH₂-” fragments.

Herein, the compound of the formula (I) of the present disclosure is also referred to as a PROTAD (small) molecule, a PROTAD compound as an ALK protein degradation agent, a PROTAD compound, a degradation agent, ALK PROTAD (compound(s)) or an ALK protein modulator, which can be used interchangeably.

Herein, the structure represented by formula (Ia) as described above is a monovalent chemical moiety (or a monovalent group) formed or derived from Crizotinib by removing a single hydrogen atom on the nitrogen of piperidinyl. The structure represented by formula (Ib) as described above is a monovalent chemical moiety (or a monovalent group) derived from Ceritinib by removing a single hydrogen atom on the nitrogen of piperidinyl.

Herein, the structures represented by formulae (Ic), (Id), and (le) as described above are all analogs of Alectinib.

Herein, the structures represented by the formulas (If), (Ig), and (Ih) as described above are all analogs of Brigatinib.

Herein, the structure represented by the formula (Ii) is a monovalent chemical moiety (or a monovalent group) derived from TAE684 (NVP-TAE684) by removing the methyl group on the nitrogen of piperazinyl.

Herein, the structure represented by the formula (Ij) is a monovalent chemical moiety (or a monovalent group) derived from ASP3026 by removing the methyl group on the nitrogen of piperazinyl.

Herein, the structure represented by formula (Ik) is a monovalent chemical moiety (or a monovalent group) derived from GSK1838705A by removing one or two methyl groups on the dimethylamino group.

Herein, the structure represented by the formula (Ii) is a monovalent chemical moiety (or a monovalent group) derived from AZD3463 by removing a single hydrogen atom from the primary amine group (—NH₂).

Herein, the structure represented by formula (Im) is a monovalent chemical moiety (or a monovalent group) derived from Entrectinib (RXDX-101) by removing the methyl group on the nitrogen of piperazinyl.

Herein, the structure represented by formula (In) is a monovalent chemical moiety (or a monovalent group) derived from Ensartinib (X-396) by removing a single hydrogen atom on the nitrogen of piperazinyl.

Herein, a bond interrupted by a wavy line shows the point of attachment of the radical depicted. For example, the group depicted below

is the chemical moiety represented by formula (Ia), which is connected to the rest part of the compound of formula (I) through the N atom of piperidinyl.

Herein, the ULM can represents a structure of the following formula (II)

wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group or is absent. The structure of the following formula (II) is a derivative of Thalidomide, Lenalidomide, or Pomalidomide.

Herein, the ULM can also represents a structure of the following formula (III)

where Z represents a carbonyl group or is absent. The structure of the following formula (III) is a derivative of VHL-1.

As used herein, the terms “LIN” and “linker” are used interchangeably and both refers to a linking group in a compound of formula (I).

As used herein, the term “intermediate LM” refers to an intermediate compound in the following schemes for synthesizing the target compounds of the present disclosure by reacting with ALK-TKIs, for example, Brigatinib derivatives, Erlotinib derivatives, Ceritinib, or Crizotinib derivatives.

As used herein, the term “halogen atom” or “halogen” used alone or in combination refers to fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.

As used herein, the term “alkyl” used alone or in combination refers to a linear or branched alkyl group. The term “(C_(x)-C_(y)) alkyl” or “C_(x-y) alkyl” (x and y are each an integer) refers to a linear or branched chain alkyl group containing x to y carbon atoms. The term “C₁₋₁₀ alkyl” used alone or in combination in the present disclosure refers to a linear or branched chain alkyl group containing 1 to 10 carbon atoms. The C₁₋₁₀ alkyl group of the present disclosure includes, but are not limited to, a C₁₋₉ alkyl group, or a C₁₋₈ alkyl group, or a C₂₋₈ alkyl group, or a C₁₋₇ alkyl group, or a C₁₋₆ alkyl, C₁₋₅ alkyl, or C₁₋₄ alkyl. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term “C₁₋₃ alkyl group” in the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms, and its representative examples include methyl, ethyl, n-propyl, and isopropyl.

As used herein, the “alkyl” is optionally substituted, and the substituent can be one or more selected from the group consisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, heterocyclyl, or any combination thereof.

As used herein, the term “alkylene” (which is used interchangeably with “alkylene chain”) used alone or in combination refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term “C_(x)-C_(y) alkylene” or “C_(x-y) alkylene” (x and y are each an integer) refers to a linear or branched alkylene group containing from x to y carbon atoms. The C₁₋₃₀ alkylene group in the present disclosure includes, but are not limited to, C₁-C₂₉ alkylene, C₁-C₂₈ alkylene, C₁-C₂₇ alkylene, C₁-C₂₆ alkylene, C₁-C₂₅ alkylene, C₁-C₂₄ alkylene, C₁-C₂₃ alkylene, C₁-C₂₂ alkylene, C₁-C₂₁ alkylene, C₁-C₂₀ alkylene, C₁-C₁₉ alkylene, C₁-C₈ alkylene, C₁-C₁₇ alkylene, C₁-C₁₆ alkylene, C₁-C₁₅ alkylene, C₁-C₁₄ alkylene, C₁-C₁₃ alkylene, C₁-C₁₂ alkylene, C₁-C₁₁ alkylene, C₁-C₁₀ alkylene, C₁-C₉ alkylene, C₁-C₈ alkylene, C₁-C₇ alkylene, C₁-C₆ alkylene, C₁-C₅ alkylene, C₁-C₄ alkylene, C₁-C₃ alkylene, or C₁-C₂ alkylene.

Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene.

As used herein, the term “aryl” used alone or in combination refers to a monovalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the “aryl” is an optionally substituted aryl. A substituted aryl refers to an aryl group optionally substituted 1-3 times with a substituent(s) (that is, the aryl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “arylene” used alone or in combination refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene group, naphthylene group or fluorenylene group. In the present disclosure, the “arylene” is an optionally substituted arylene. A substituted arylene group refers to an arylene group optionally substituted 1-3 times with a substituent(s) (that is, the arylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “C₁₋₃ alkoxy group” used alone or in combination refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C₁₋₃ alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.

As used herein, the term “cycloalkyl” used alone or in combination refers to a saturated or partially unsaturated (e.g., containing one or more double bonds, but not having a completely conjugated π-electron system) monovalent monocyclic or bicyclic cyclic hydrocarbon radical, which may include fused, bridged, or spiro ring system, having from 3 to 12 carbon atoms, e.g., having from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, and spiro-cycloalkyl. The cycloalkyl group may be unsubstituted or substituted. A substituted cycloalkyl group refers to a cycloalkyl group optionally substituted 1-3 times by a substituent(s) (that is, the cycloalkyl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “cycloalkylene”, used alone or in combination, refers to a saturated and partially unsaturated (e.g., containing one or more double bonds, but not having a fully conjugated π-electron system) divalent monocyclic or bicyclic cyclic hydrocarbon group, which may include fused, bridged, or spiro ring system, having from 3 to 12 carbon atoms, e.g., having from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms.

Representative examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, and spiro-cycloalkylene. The cycloalkylene group may be unsubstituted or substituted. A substituted cycloalkylene group refers to a cycloalkylene group optionally substituted 1-3 times by a substituent(s) (that is, the cycloalkylene group optionally has 1-3 same or different substituent(s)).

In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “heteroaryl” used alone or in combination refers to a 5- to 10-membered monovalent monocyclic or bicyclic aromatic ring containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 4H-fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. According to a clear definition, heteroaryl groups may be unsubstituted or substituted. A substituted heteroaryl group refers to a heteroaryl group optionally substituted 1-3 times with a substituent(s) (that is, the heteroaryl group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “heteroarylene” used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridinylene, 1H-pyrrolo[3,2-b]pyridinylene, 1H-pyrrolo[2,3-b]pyridinylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. According to a clear definition, the heteroarylene group may be unsubstituted or substituted. A substituted heteroarylene group refers to a heteroarylene group optionally substituted 1-3 times by a substituent(s) (that is, the heteroarylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “heterocyclyl” used alone or in combination refers to a 4- to 6-membered saturated monocyclic monovalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 4, or from 1 to 3, or from 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxanyl. The heterocyclyl may be unsubstituted or substituted as explicitly defined. A substituted heterocyclyl group refers to a heterocyclyl group optionally substituted 1-3 times with a substituent(s) (that is, the heterocycloalkylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent may be any one optionally selected from the group consisting of C₁-3 alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxy, or any combination thereof.

As used herein, the term “heterocyclylene” used alone or in combination refers to a 4- to 6-membered saturated monocyclic divalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 4, or from 1 to 3, or from 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclylene group include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, triazolylend, tetrahydrofuranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, and dioxanylene. The heterocyclylene group may be unsubstituted or substituted as explicitly defined. A substituted heterocycloalkylene refers to a heterocycloalkylene group optionally substituted 1-3 times by a substituent(s) (that is, the heterocycloalkylene group optionally has 1-3 same or different substituent(s)). In a further embodiment, the substituent can be any one optionally selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, hydroxyl, or any combination thereof.

As used herein, the term “spiro-cycloalkylene” used alone or in combination refers to a divalent alicyclic hydrocarbon group derived by removing two hydrogen atoms from any one or two free valence carbon atom(s) of the alicyclic hydrocarbon group in which two rings share one common carbon atom. Representative examples include, but are not limited to, spiro[3.3]heptanylene (for example

spiro[4.5]decanylene, spiro[5.5]undecanylene, 4-methylspiro[2.4] heptanylene etc.

As used herein, the term “alkynyl” used alone or in combination refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms.

Examples of the alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-dialkynyl.

As used herein, the term “alkynylene” used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkynylene group include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

As used herein, the term “alkenyl” used alone or in combination refers to a linear or branched monovalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkenyl group include, but are not limited to, vinyl, 1-propenyl, and 1-butenyl.

As used herein, the term “alkenylene” used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4, or from 2 to 3, or 2) carbon atoms. Examples of the alkenylene group include, but are not limited to, vinylidene (e.g., —CH═CH—), 1-propenylene, and 1-butenylene.

Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula I according to the disclosure are also encompassed within the scope of the invention.

In all embodiments of the disclosure, the salt or pharmaceutically acceptable salt of the compound of formula I refers to a non-toxic inorganic or organic acid and/or base addition salt. Examples include, but are not limited to, sulfate, hydrochloride, citrate, maleate, sulfonate, or p-toluenesulfonate etc.

“Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be “acceptable.” Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other common non-toxic compatible substances used in pharmaceutical preparations.

A “therapeutically effective amount” of a compound of the disclosure depends on the age, sex, and weight of the patient, the patient's current medical condition, and the cancer progression of the patient being treated. Those skilled in the art will be able to determine a suitable dosage based on these and other factors.

The term “room temperature” used herein refers to the ambient temperature, such as a temperature of 20-30° C.

The compound developed by the present invention belongs to a specific protein-degrading agent, which is composed of three parts: a target protein anchoring part, a protein degradation system (such as an E3 ligase) recruitment part, and a linker. In the present disclosure, an inhibitor targeting ALK protein is selected as an anchoring part, and an E3 ligase ligand is combined with an ALK protein inhibitor through a linker to develop a degradation agent targeting ALK protein. Through the specific recognition of target proteins by ALK-TKIs, the tyrosine kinase activity of ALK is inhibited, and at the same time, E3 ligase specifically ubiquitinates ALK protein to achieve degradation and elimination, and finally can remove the target protein from tumor cells. Because ALK mutation-positive lung cancer cells are highly dependent on the presence and activity of ALK protein, completely degrading ALK protein and inhibiting residual ALK activity can not only inhibit tumorigenesis and progression, but also potentially overcome resistance to targeted drugs. In addition, the degrading agent designed and developed by the present invention can also target and inhibit other tyrosine kinase receptors including ROS1, c-MET, insulin receptor, IGFIR and EGFR with lung cancer drivering mutation, etc. The compounds developed by the present invention provide potentially alternative treatments for cancers that are positive for these targets. This research will provide a new treatment strategy for lung cancer patients in the context of precision medicine.

EXAMPLES

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. The invention may be practiced without some or all of these specific details. In other cases, well-known process operations have not been described in detail in order not to unnecessarily obscure the present invention. Although the present invention will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present invention to these embodiments.

The following abbreviations are used throughout the description and examples:

Boc Tert-butoxycarbonyl

Con. concentration

DCM Dichloromethane DMF N, N-dimethylformamide

DMSO Dimethyl sulfoxide

DIPEA N, N-diisopropylethylamine

EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide ESI Electrospray ionization equiv equivalent

EtOH Ethanol

HOAT 1-hydroxy-7-azobenzotriazole HPLC High performance liquid chromatography HRMS High resolution mass spectrometry LC-MS Liquid chromatography-mass spectrometry LRMS Low resolution mass spectrometry LC Liquid chromatography Me methyl

MeCN Acetonitrile MeOH Methanol

MS Mass spectrometry MW microwave

NMM N-methylmorpholine NMP N-methylpyrrolidone

¹H NMR Proton nuclear magnetic resonance rt Room temperature

TFA Trifluoroacetate

TLC Thin layer chromatography

TMS Trimethylsilyl

Xantphos; or X-Phos 4,5-bis (diphenylphosphine)-9,9-dimethylxanthene

In the present disclosure, the ¹H NMR spectrum is measured using a Bruker-500 MHz nuclear magnetic resonance instrument, and CD₃OD containing 0.1% TMS is used as a solvent, wherein the ¹H NMR spectrum uses CD3OD (δ=3.31 ppm) as an internal standard; or CDCl₃ containing 0.1% TMS is used as the solvent, wherein the ¹H NMR spectrum uses CDCl₃ (δ=7.26 ppm) as the internal standard; or DMSO-d₆ containing 0.03% TMS as the solvent, wherein the ¹H NMR spectrum uses DMSO-d₆ (δ=2.50 ppm) as the internal standard; LRMS spectrum was measured on an AB Triple 4600 mass spectrometer, HPLC preparation was measured on a SHIMADZU LC-20AP type instrument, and HPLC purity was measured on a SHIMADZU LC-30AP or Waters 1525 type instrument. All reactions were performed in the air without special instructions; the reactions were followed by TLC or LC-MS.

Solvents and reagents are processed as follows:

The solvents used in the reaction: DCM, DMF, anhydrous EtOH, and anhydrous MeOH were purchased from Chinese Sinopharm Group;

Preparative grade CH₃CN and deionized water are used in HPLC preparation;

Unless otherwise stated, Alectinib, Alectinib analogue A, Crizotinib, Ceritinib, Brigatinib, TAE684 (NVP-TAE684), ASP3026, GSK1838705A, AZD3463, Entrectinib (RXDX-101), Ensartinib (X-396)) and various kinds of carbon chain linking unit (linker group of the compound of the formula (I) of the present disclosure) were directly purchased.

Other reagents and medicines were purchased from the manufacturer and used directly without special instructions.

General Synthesis Procedure General Synthesis Procedure for Brigatinib Analogue a, B, C (ALK Inhibitors)

Wherein group X and Y are as shown in Scheme 1.

General Synthesis Procedure for Alectinib Analogue B, C (ALK Inhibitors):

Wherein group X and Y are as shown in Scheme 2.

In addition, the Alectinib amalogue A (9-ethyl-6,6-dimethyl-11-oxo-8-(piperazin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile) can also be purchased directly.

General Synthesis Procedure for Intermediate LM (Pomalidomide PEG Linker):

Wherein n is an integer of from 1 to 5, as shown in Scheme 3.

General Synthesis Procedure for Intermediate LM (Pomalidomide Alkyl Carbon Chain Linker)

Wherein n is an integer of from 0 to 5, as shown in Scheme 4.

General Synthesis Procedure for Intermediate LM (VHL-1 PEG Linker):

Wherein n is an integer of from 0 to 10, as shown in Scheme 5.

General Synthesis Procedure for Intermediate LM (VHL-1 Alkyl Carbon Chain Linker):

Wherein n is an integer of from 0 to 7, as shown in Scheme 6.

General Synthesis Procedure for Intermediate LM (Lenalidomide Carbonyl Alkyl Carbon Chain Linker):

Wherein n is an integer of from 1 to 5, as shown in Scheme 7.

General Synthesis Procedure for Intermediate LM (Lenalidomide Alkyl Carbon Chain Linker)

Wherein n is an integer of from 1 to 20, as shown in Scheme 8.

General Synthesis Procedure for Special Intermediate LM (SIAIS151103):

General Synthesis Procedure for Special Intermediate LM (SIAIS164119):

General Synthesis Procedure for Special Intermediate LM (SIAIS164050):

General Synthesis Procedure for Special Intermediate LM (SIAIS164128):

General Synthesis Procedure for Special Intermediate LM (SIAIS219048):

Wherein n is 7, as shown in Scheme 13.

General Synthesis Procedure for Special Intermediate LM (SIAIS172147):

General Synthesis Procedure for Compounds in this Patent:

INTERMEDIATE EXAMPLES Intermediate Example 1: Synthesis of Brigatinib Analogue A (SIAIS1197135)

Brigatinib Analogue A (SIAIS1197135) was synthesized according to scheme 1.

Synthesis of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS1197111)

To a solution of 5-fluoro-2-nitroanisole (7 g, 40.9 mmol) in DMF (60 mL) were added K₂CO₃ (8.4 g, 60.8 mmol) and tert-butyl piperazine-1-carboxylate (9.1 g, 48.9 mmol) at room temperature under air. After stirring at the same temperature overnight, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by recrystallization (eluent: petroleum ether/ethyl acetate=5:1) to afford SIAIS1197111 in 80% yield (11.1 g) as a yellow solid. ¹H NMR (500 MHz, DMSO) δ 7.89 (d, J=9.3 Hz, 1H), 6.57 (d, J=9.5 Hz, 1H), 6.52 (s, 1H), 3.90 (s, 3H), 3.46 (s, 8H), 1.42 (s, 9H). HRMS (ESI) calcd for C₁₆H₂₄N₃O₅ ⁺ [M+H]⁺, 338.1710; found, 338.1610.

Synthesis of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (SIAIS1197129)

To a stirred solution of SIAIS1197111 (10 g, 29.6 mmol) in EtOH (90 mL) and H₂O (30 mL) were added NH₄Cl (6.3 g, 118.6 mmol) and Fe powder (8.3 g, 148.2 mmol). Then the resulting mixture was refluxed at 80° C. for 2 h under an atmosphere of nitrogen. When the reaction was complete, the crude mixture was cooled down to room temperature, filtered by silica, after solvent evaporation, extracted with DCM (3×50 mL), the combined organic layer was washed with brine (20 mL), then dried over Na₂SO₄ and concentrated in vacuum to afford SIAIS1197129 in 85% yield (7.7 g) as a gray solid. ¹H NMR (500 MHz, MeOD) δ 6.72 (d, J=8.3 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 6.47 (d, J=7.0 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 4H), 2.99 (s, 4H), 1.50 (s, 9H). HRMS (ESI) calcd for C₁₆H₂₆N₃O₃ ⁺ [M+H]⁺, 308.1969; found, 308.1882.

Synthesis of (2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) dimethylphosphine oxide. (SIAIS1197135)

To a solution of 2,5-dichloro-N-(2-(dimethylphosphoryl)phenyl)pyrimidin-4-amine (2 g, 6.3 mmol) in DMF (30 mL) were added SIAIS1197129 (2.4 g, 7.8 mmol), Pd(OAc)₂ (176 mg, 0.78 mmol), Xantphos (810 mg, 1.4 mmol) and Cs₂CO₃(6.4 g, 19.6 mmol) in microwave tube, the solution was purged and refilled with nitrogen three times. Then the mixture was stirred at 110° C. for 2 h in the microwave. After the starting material was consumed, the reaction mixture was filtered through a pad of silica gel and most of the solvent of the filtrate was removed under the reduced pressure. Then the mixture was quenched with water, extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by reverse phase ISCO (C18) to give the title compound (900 mg) as a brown solid.

To a solution of above compound (900 mg) in DCM (6 mL) was added TFA (2 mL) under air. The resulting solution was stirred at room temperature for 1 h. Then most of the solvent was removed under the reduced pressure, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, then extracted with DCM, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by reverse phase ISCO (C18), eluent (v/v): MeOH/water=10%-100%, to afford SIAIS1197135 as a yellow solid (701 mg, 23% yield over two steps). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J=8.2, 4.4 Hz, 1H), 8.04 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.61 (dd, J=14.1, 7.7 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.26 (t, J=7.5, 1H), 6.67 (d, J=2.5 Hz, 1H), 6.45 (dd, J=8.8, 2.5 Hz, 1H), 3.86 (s, 3H), 3.24-3.17 (m, 4H), 3.17-3.11 (m, 4H), 1.83 (d, J=13.5 Hz, 6H). HRMS (ESI) calcd for C₂₃H₂₉ClN₆O₂P⁺ [M+H]⁺, 487.1773; found, 487.1773.

Intermediate Example 2: Synthesis of Brigatinib Analogue B

Brigatinib Analogue B was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1, the synthesis data and structural characterization data are as follows:

tert-butyl (1-(3-methoxy-4-nitrophenyl)piperazine-4-yl) carbamate (SIAIS151054)

(yellow solid, 1.81 g, 88%)¹H NMR (500 MHz, CDCl₃) δ 7.99 (t, J=8.9 Hz, 1H), 6.41 (dd, J=9.4, 2.5 Hz, 1H), 6.30 (d, J=2.5 Hz, 1H), 4.49 (s, 1H), 3.94 (s, 3H), 3.86-3.82 (m, 2H), 3.71 (s, 1H), 3.09-3.00 (m, 2H), 2.11-2.03 (m, 2H), 1.89-1.75 (m, 2H), 1.45 (s, 9H).

tert-butyl (1-(4-amino-3-methoxyphenyl)piperazine-4-yl)carbamate (SIAIS151062)

(gray solid, 411.6 mg, 90%)¹H NMR (500 MHz, DMSO) δ 6.82 (d, J=7.6 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 6.28 (dd, J=8.4, 2.4 Hz, 1H), 4.20 (s, 2H), 3.73 (s, 3H), 3.33-3.26 (m, 3H), 2.56-2.50 (m, 2H), 1.77 (d, J=11.4 Hz, 2H), 1.53-1.45 (m, 2H), 1.39 (s, 9H).

(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS151101)

(yellow solid, 330 mg, 33% yield over two steps)¹H NMR (500 MHz, DMSO) δ 8.49 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.53 (ddd, J=14.0, 7.7, 1.3 Hz, 1H), 7.38-7.32 (m, 2H), 7.10 (t, J=7.1 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 6.46 (dd, J=8.7, 2.5 Hz, 1H), 3.75 (s, 3H), 3.65-3.61 (m, 2H), 2.78-2.67 (m, 3H), 1.82-1.79 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.42-1.34 (m, 2H). HRMS (ESI) calcd for C₂₄H₃₁ClN₆O₂P [M+H]⁺: 501.1913, found, 501.1900.

Intermediate Example 3: Synthesis of Brigatinib Analogue C

Brigatinib Analogue C was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1, the synthesis data and structural characterization data are as follows:

tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (SIAIS151059)

(yellow solid, 1.02 g, 83%)¹H NMR (500 MHz, MeOD) δ 7.93 (d, J=9.4 Hz, 1H), 6.55 (dt, J=13.4, 6.7 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 4.10 (s, 1H), 4.07 (s, 1H), 3.94 (d, J=6.6 Hz, 3H), 3.43 (s, 4H), 3.02-2.93 (m, 2H), 2.60-2.55 (m, 5H), 2.02-1.95 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H), 1.46 (s, 9H). HRMS (ESI) calcd for C₂₁H₃₃N₄O₅ [M+H]⁺: 421.2445, found, 421.2442.

tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (SIAIS164003)

(gray solid, 745 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 6.59 (t, J=56.8 Hz, 3H), 3.78 (s, 3H), 3.46 (s, 6H), 2.62 (d, J=4.3 Hz, 6H), 2.42 (s, 1H), 1.98 (s, 2H), 1.69 (d, J=9.7 Hz, 2H), 1.46 (s, 9H). HRMS (ESI) calcd for C₂₁H₃₅N₄O₃ [M+H]⁺: 391.2704, found, 391.3048.

(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. (SIAIS164005)

(yellow solid, 350 mg, 37% yield over two steps). ¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J=8.2, 4.4 Hz, 1H), 8.03 (s, 1H), 7.69-7.64 (m, 1H), 7.60 (ddd, J=14.0, 7.7, 1.4 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.26 (td, J=7.6, 1.2 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.45 (dd, J=8.8, 2.5 Hz, 1H), 3.85 (s, 3H), 3.73-3.63 (m, 2H), 3.11-3.02 (m, 4H), 2.79-2.66 (m, 6H), 2.48-2.43 (m, 1H), 1.99 (d, J=12.5 Hz, 2H), 1.84 (d, J=13.5 Hz, 6H), 1.72-1.63 (m, 2H). HRMS (ESI) calcd for C₂₈H₃₈ClN₇O₂P [M+H]⁺: 570.2508, found, 570.2498.

Intermediate Example 4: Synthesis of Alectinib Analogue B (SIAIS184193)

Alectinib Analogue B 8-(4-aminopiperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (SIAIS184193) was synthesized according to scheme 2:

At room temperature, 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (440 mg, 1 mmol), 4-tert-butoxycarbonylaminopiperidine (377 mg, 1.4 mmol), Pd₂(dba)₃ (45.8 mg, 0.05 mmol), Sphos (82.1 mg, 0.2 mmol) anad dioxane (10 mL) was added sequentially in a 25 mL egg-shaped flask, the mixture was evacuated and replaced with argon, then NaHMDS (4 mL, 4 mmol, 1.0 M in THF) was added, the mixture was heated to 60° C. and stirred for 5 h. When the reaction was complete detected by TLC, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent: hexanes/EA=1:1) to give a brown solid.

To a solution of above brown solid (350 mg) in DCM (6 mL) was added TFA (2 mL) under air. The resulting solution was stirred at room temperature for 1 h. Then most of the solvent was removed under the reduced pressure, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, extracted with DCM, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase ISCO (C18), eluent (v/v): MeOH/water=10%-100%, to afford the desired product SIAIS184193 as yellow solid (310 mg, 60% over 2 steps). ¹H NMR (500 MHz, DMSO) δ 12.91 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.17 (d, J=4.2 Hz, 2H), 8.05 (d, J=8.2 Hz, 1H), 8.01 (s, 1H), 7.61 (dd, J=8.1, 1.3 Hz, 1H), 7.38 (s, 1H), 3.22 (d, J=12.2 Hz, 3H), 2.86 (t, J=11.4 Hz, 2H), 2.70 (q, J=7.5 Hz, 2H), 2.06 (d, J=10.0 Hz, 2H), 1.81-1.73 (m, 8H), 1.28 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₂₆H₂₉N40 [M+H]⁺: 413.2336, found 413.2339.

Intermediate Example 5: Synthesis of Alectinib Analogue C

Alectinib Analogue C was synthesized according to scheme 2, using similar procedures for the preparation of Alectinib Analogue B in Intermediate Example 4, the structural characterization data are as follows:

9-ethyl-6,6-dimethyl-11-oxo-8-(4-(piperazin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo [b]carbazole-3-carbonitrile. (SIAIS184192)

(yellow solid, 280 mg, 48%)¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 3.94 (s, 8H), 3.61 (s, 1H), 3.49-3.29 (m, 4H), 2.70 (q, J=7.8 Hz, 2H), 1.76 (s, 6H), 1.61 (s, 4H), 1.28 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₃₀H₃₆N50 [M+H]⁺: 482.2914, found 482.2911.

Intermediate Example 6: Synthesis of 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (SIAIS151001)

According to Scheme 3, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (5 mmol, 1 equiv), tert-butyl 3-(2-aminoethoxy)propionate (6 mmol, 1.2 equiv) and DIPEA (25 mmol, 5 equiv) in NMP (8 mL) was stirred in a 30 mL microwave tube for 10 min at room temperature, then charged with argon and heated to 110° C. in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with EA (4×50 mL), the combined organic phase was washed with water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexanes/EA=1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151001 was obtained as yellow solid (1.0 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 11.09 (s, 1H), 7.57 (dd, J=8.5, 7.5 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.59 (t, J=5.7 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.65 (t, J=6.3 Hz, 2H), 3.59 (t, J=5.5 Hz, 2H), 3.46 (q, J=5.5 Hz, 2H), 2.91-2.83 (m, 1H), 2.61-2.52 (m, 2H), 2.46 (t, J=6.3 Hz, 2H), 2.05-2.00 (m, 1H); HRMS (ESI) calcd for C₁₈H₂₀N₃O₇ ⁺ [M+H]⁺, 390.1301; found, 390.1261.

Intermediate Example 7: Synthesis of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (SIAIS151004)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate was used to prepare SIAIS151004 (yellow solid, 0.95 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J=8.0, 7.5 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.60 (t, J=5.7 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.62-3.58 (m, 4H), 3.56-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.46 (dd, J=11.1, 5.5 Hz, 2H), 2.92-2.84 (m, 1H), 2.66-2.51 (m, 2H), 2.42 (t, J=6.4 Hz, 2H), 2.06-1.98 (m, 1H); HRMS (ESI) calcd for C₂₀H₂₄N₃O₈ ⁺ [M+H]⁺, 434.1558; found, 434.1445.

Intermediate Example 8: Synthesis of 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (SIAIS151005)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate was used to prepare SIAIS151005 (yellow solid, 0.95 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J=8.0, 7.0 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.61 (t, J=5.8 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.63-3.48 (m, 14H), 2.92-2.83 (m, 1H), 2.64-2.52 (m, 2H), 2.18 (t, J=8.1 Hz, 2H), 2.07-1.99 (m, 1H). HRMS (ESI) calcd for C₂₂H₂₈N₃O₉ ⁺ [M+H]⁺, 478.1820; found, 478.1159.

Intermediate Example 9: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (SIAIS151006)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-oate was used to prepare SIAIS151006 (yellow solid, 0.87 g, 53% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J=8.5, 7.5 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.60 (t, J=5.7 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.63-3.48 (m, 18H), 2.92-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.41 (t, J=6.4 Hz, 2H), 2.07-1.98 (m, 1H). HRMS (ESI) calcd for C₂₄H₃₂N₃O₁₀ ⁺ [M+H]⁺, 522.2082; found, 522.2178.

Intermediate Example 10: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (SIAIS151007)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 1-amino-3,6,9,12,15-pentaoxaoctadecan-18-oate was used to prepare SIAIS151007 (yellow solid, 0.8 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.60 (t, J=5.7 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.63-3.54 (m, 8H), 3.54-3.48 (m, 12H), 3.30 (dd, J=7.0 Hz, 4H), 2.92-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.06-1.99 (m, 1H). HRMS (ESI) calcd for C₂₆H₃₆N₃O₁₁ ⁺ [M+H]⁺, 566.2344; found, 566.2679.

Intermediate Example 11: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (SIAIS151025)

According to Scheme 4, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (7 mmol, 1 equiv), tert-butyl 3-(2-aminoethoxy)propionate (8.4 mmol, 1.2 equiv) and DIPEA (35 mmol, 5 equiv) in NMP (8 mL) was stirred in a microwave tube for 10 min at room temperature, then charged with argon and heated to 110° C. in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with ethyl acetate (4×50 mL), the combined organic phase was washed with water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent (v/v): hexanes/EA=1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151025 was obtained as yellow solid (1.2 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 7.59 (dd, J=15.9, 8.5 Hz, 1H), 7.07 (d, J=7.0 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.86 (t, J=5.7 Hz, 1H), 5.06 (dt, J=15.1, 7.6 Hz, 1H), 4.08 (d, J=5.7 Hz, 2H), 2.92-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.07-2.02 (m, 1H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M+H]⁺, 332.0877; found, 332.0720.

Intermediate Example 12: Synthesis of 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (SIAIS151026)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 3-amino-propanoate was used to prepare SIAIS151026 (yellow solid, 0.93 g, 39% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.59 (dd, J=8.0, 7.5 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.67 (t, J=6.0 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.53 (dd, J=12.6, 6.3 Hz, 2H), 2.92-2.84 (m, 1H), 2.65-2.53 (m, 4H), 2.08-1.98 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M+H]⁺, 346.1034; found, 346.0868.

Intermediate Example 13: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (SIAIS151019)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 4-amino-butanoate was used to prepare SIAIS151019 (yellow solid, 0.8 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 12.14 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J=8.4, 7.3 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.65 (t, J=6.0 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.32 (dd, J=13.7, 6.7 Hz, 2H), 2.94-2.82 (m, 1H), 2.66-2.51 (m, 2H), 2.30 (t, J=7.2 Hz, 2H), 2.05-2.00 (m, 1H), 1.82-1.75 (m, 2H). HRMS (ESI) calcd for C₁₇H₁₈N₃O₆ ⁺ [M+H]⁺, 360.1190; found, 360.1223.

Intermediate Example 14: Synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (SIAIS151020)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 5-amino-pentanoate was used to prepare SIAIS151020 (yellow solid, 0.9 g, 50% yield). ¹H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 11.11 (s, 1H), 7.57 (dd, J=8.3, 7.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.56 (t, J=5.9 Hz, 1H), 5.05 (dd, J=12.7, 5.4 Hz, 1H), 3.32-3.28 (m, 2H), 2.94-2.82 (m, 1H), 2.62-2.51 (m, 2H), 2.27-2.25 (m, 2H), 2.06-1.99 (m, 1H), 1.62-1.53 (m, 4H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M+H]⁺, 374.1347; found, 374.1384.

Intermediate Example 15: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (SIAIS151027)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 6-amino-hexanoate was used to prepare SIAIS151027 (yellow solid, 1.26 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 12.00 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J=8.3, 7.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.54 (t, J=5.9 Hz, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.30-3.27 (m, 2H), 2.92-2.84 (m, 1H), 2.63-2.51 (m, 2H), 2.21 (t, J=7.5 Hz, 2H), 2.08-1.98 (m, 1H), 1.60-1.50 (m, 4H), 1.38-1.31 (m, 2H). HRMS (ESI) calcd for C₁₉H₂₂N₃O₆ ⁺ [M+H]⁺, 388.1503; found, 388.1119.

Intermediate Example 16: Synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (SIAIS151086)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 7-amino-heptanoate was used to prepare SIAIS151086 (yellow solid, 1.3 g, 64% yield). ¹H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J=8.3, 7.3 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 5.05 (dd, J=12.7, 5.4 Hz, 1H), 3.28 (dd, J=13.4, 6.7 Hz, 2H), 2.94-2.82 (m, 1H), 2.65-2.51 (m, 2H), 2.19 (t, J=7.3 Hz, 2H), 2.05-2.00 (m, 1H), 1.60-1.53 (m, 2H), 1.53-1.46 (m, 2H), 1.37-1.28 (m, 4H). HRMS (ESI) calcd for C₂₀H₂₄N₃O₆ ⁺ [M+H]⁺, 402.1660; found, 402.1643.

Intermediate Example 17: Synthesis of 2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetic acid (SIAIS151010)

According to scheme 5, to a solution of diacid (2,2′-(ethane-1,2-diylbis(oxy))diacetic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), VHL-1 (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0° C. The resulting reaction solution was stirred at 0° C. for 5 h and then at room temperature overnight. After VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS151010 as white solid (0.2 g, 23%). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.60 (t, J=5.9 Hz, 1H), 7.48 (d, J=9.5 Hz, 1H), 7.40 (s, 4H), 4.57 (d, J=9.6 Hz, 1H), 4.47-4.37 (m, 2H), 4.35 (s, 1H), 4.29-4.22 (m, 1H), 4.07 (d, J=12.5 Hz, 1H), 3.97 (s, 2H), 3.69-3.59 (m, 8H), 2.44 (s, 3H), 2.07-2.03 (m, 1H), 1.93-1.87 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₂₈H₃₉N₄O₈S⁺ [M+H]⁺, 591.2483; found, 591.2365.

Intermediate Example 18: Synthesis of 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid (SIAIS151002)

According to the procedures for the preparation of Intermediate Example 17, 3,3′-(ethane-1,2-diylbis(oxy))dipropionic acid was used to prepare SIAIS151002 (white solid, 0.53 g, 44% yield). ¹H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 8.99 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 7.92 (d, J=9.3 Hz, 1H), 7.41 (dd, J=18.5, 8.2 Hz, 4H), 4.55 (d, J=9.5 Hz, 1H), 4.46-4.40 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J=15.8, 5.4 Hz, 1H), 3.69-3.56 (m, 7H), 3.49-3.46 (m, 4H), 2.58-2.53 (m, 1H), 2.47-2.42 (m, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 1H), 2.06-2.01 (m, 1H), 1.95-1.88 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₃N₄O₈S⁺ [M+H]⁺, 619.2796; found, 619.2973.

Intermediate Example 19: Synthesis of (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid (SIAIS151003)

According to the procedures for the preparation of Intermediate Example 17, 3,3′-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid was used to prepare SIAIS151003 (white solid, 0.63 g, 59% yield). ¹H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 7.92 (d, J=9.4 Hz, 1H), 7.41 (dd, J=18.5, 8.2 Hz, 4H), 4.56 (d, J=9.4 Hz, 1H), 4.47-4.41 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J=15.9, 5.5 Hz, 1H), 3.70-3.57 (m, 8H), 3.51-3.47 (m, 7H), 2.58-2.52 (m, 1H), 2.47-2.42 (m, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 1H), 2.08-2.00 (m, 1H), 1.94-1.88 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₇N₄O₉S⁺ [M+H]⁺, 663.3058; found, 663.3008.

Intermediate Example 20: Synthesis of (S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azaicosanoic acid (SIAIS151008)

According to the procedures for the preparation of Intermediate Example 17, 4,7,10,13-tetraoxahexadecanedioic acid was used to prepare SIAIS151008 (white solid, 0.53 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.4 Hz, 1H), 7.40 (dd, J=18.8, 8.3 Hz, 4H), 4.55 (d, J=9.4 Hz, 1H), 4.45-4.40 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J=15.8, 5.5 Hz, 1H), 3.69-3.54 (m, 10H), 3.48 (d, J=2.7 Hz, 9H), 2.56-2.52 (m, 1H), 2.45-2.41 (m, 2H), 2.45 (s, 3H), 2.38-2.32 (m, 1H), 2.06-2.00 (m, 1H), 1.94-1.88 (m, 1H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₄H₅₁N₄O₁₀S⁺ [M+H]⁺, 707.3320; found, 707.2945.

Intermediate Example 21: Synthesis of (S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoic acid (SIAIS151009)

According to the procedures for the preparation of Intermediate Example 17, 4,7,10,13,16-pentaoxanonadecanedioic acid was used to prepare SIAIS151009 (white solid, 0.82 g, 85% yield). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.40 (dd, J=18.6, 7.9 Hz, 4H), 4.55 (d, J=9.3 Hz, 1H), 4.47-4.40 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J=15.7, 5.2 Hz, 1H), 3.68-3.56 (m, 11H), 3.51-3.49 (s, 9H), 2.56-2.53 (m, 1H), 2.45-2.41 (m, 5H), 2.44 (s, 3H), 2.36 (dd, J=13.4, 7.0 Hz, 1H), 2.08-2.00 (m, 1H), 1.94-1.86 (m, 1H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₆H₅₅N₄O₁₁S⁺ [M+H]⁺, calcd for 751.3583; found, 751.3199.

Intermediate Example 22: Synthesis of 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SIAIS074011)

According to scheme 6, to a solution of diacid (succinic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), VHL-1 (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0° C. The resulting reaction solution was stirred at 0° C. for 5 h and then at room temperature overnight. After VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS074011 as white solid (0.82 g, 65%). ¹H NMR (500 MHz, CDCl₃) δ 11.88 (s, 1H), 8.85 (s, J=11.2 Hz, 1H), 7.69 (s, 1H), 7.37-7.29 (m, 4H), 6.09 (br, 1H), 4.67-4.54 (m, 3H), 4.49 (s, 1H), 4.29 (dd, J=15.0, 5.0 Hz, 1H), 4.05 (d, J=11.3 Hz, 1H), 3.73-3.63 (m, 1H), 2.73-2.58 (m, 1H), 2.57-2.41 (m, 3H), 2.50 (s, 3H), 2.31-2.14 (m, 2H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₆H₃₅N₄O₆S⁺ [M+H]⁺, 531.2272; found, 531.2275.

Intermediate Example 23: Synthesis of 5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoic acid (SIAIS074012)

According to the procedures for the preparation of Intermediate Example 22, glutaric acid was used to prepare SIAIS074012 (white solid, 0.85 g, 67% yield). ¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.65 (br, 1H), 8.10 (s, 1H), 7.38-7.29 (m, 4H), 4.72-4.64 (m, 3H), 4.52 (s, 1H), 4.25 (dd, J=15.4, 5.0 Hz, 1H), 4.09 (d, J=10.5 Hz, 1H), 3.73 (d, J=10.0 Hz, 1H), 2.48 (s, 3H), 2.39-2.13 (m, 6H), 1.92-1.74 (m, 2H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₇H₃₇N₄O₆S⁺[M+H]⁺, 545.2428; found, 545.2428.

Intermediate Example 24: Synthesis of 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (SIAIS074013)

According to the procedures for the preparation of Intermediate Example 22, adipic acid was used to prepare SIAIS074013 (white solid, 0.79 g, 55% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.99 (s, 1H), 7.66 (s, 1H), 7.39-7.33 (m, 4H), 7.30 (d, J=7.5 Hz, 1H). 7.14 (br, 1H), 4.67-4.61 (m, 3H), 4.52 (s, 1H). 4.28 (dd, J=15.4, 5.0 Hz, 1H), 4.09 (d, J=11.4 Hz, 1H), 3.74-3.63 (m, 1H), 2.52 (s, 3H), 2.31-2.17 (m, 6H), 1.65-1.53 (m, 4H), 0.96 (s, 9H). HRMS (ESI) calcd for calcd for C₂₈H₄ON₄O₆S⁺ [M+H]⁺, 559.2585; found, 559.3632.

Intermediate Example 25: Synthesis of 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (SIAIS074014)

According to the procedures for the preparation of Intermediate Example 22, pimelic acid was used to prepare SIAIS074014 (white solid, 0.8 g, 57% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.90 (s, 1H), 7.42-7.38 (m, 1H), 7.41-7.33 (m, 4H), 7.31 (d, J=9.0 Hz, 1H), 6.38 (br, 1H), 4.79-4.46 (m, 3H), 4.55 (s, 1H), 4.28 (dd, J=15.2, 5.1 Hz, 1H), 4.12 (d, J=11.3 Hz, 1H), 3.72-3.63 (m, 1H), 2.51 (s, 3H), 2.38-2.33 (m, 1H), 2.28-2.21 (m, 4H), 2.18-2.12 (m, 1H), 1.62-1.52 (m, 3H), 1.33-1.23 (m, 3H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₉H₄₁N₄O₆S⁺ [M+H]⁺, 573.2741; found, 573.3804.

Intermediate Example 26: Synthesis of 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoic acid (SIAIS074015)

According to the procedures for the preparation of Intermediate Example 22, suberic acid was used to prepare SIAIS074015 (white solid, 0.95 g, 68% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 7.43 (t, J=6.0 Hz, 1H), 7.34 (s, 4H), 6.98 (d, J=8.5 Hz, 1H), 6.10 (s, 1H), 4.69-4.65 (m, 1H), 4.63-4.51 (m, 2H), 4.55-4.50 (m, 1H), 4.38-4.27 (m, 1H), 4.11 (d, J=16.7 Hz, 1H), 3.72-3.62 (m, 1H), 2.51 (s, 3H), 2.39-2.13 (m, 6H), 1.58-1.54 (m, 4H), 1.33-1.21 (m, 4H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₃N₄O₆S⁺ [M+H]⁺, 587.2898; found, 587.2917.

Intermediate Example 27: Synthesis of 9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoic acid (SIAIS074016)

According to the procedures for the preparation of Intermediate Example 22, azelaic acid was used to prepare SIAIS074016 (white solid, 0.92 g, 64% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 7.35 (s, 4H), 7.02 (t, J=14.3 Hz, 1H), 5.99 (s, 1H), 4.74-4.49 (m, 4H), 4.30 (dd, J=15.2, 5.1 Hz, 1H), 4.13 (d, J=11.3 Hz, 1H), 3.67 (dd, J=11.5, 3.5 Hz, 1H), 2.51 (s, 3H), 2.42-2.36 (m, 1H), 2.28 (t, J=7.5 Hz, 2H), 2.24-2.12 (m, 3H), 1.67-1.48 (m, 4H), 1.35-1.22 (m, 6H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₁H₄₅N₄O₆S⁺ [M+H]⁺, 601.3054; found, 601.3150.

Intermediate Example 28: Synthesis of 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoic acid (SIAIS074019)

According to the procedures for the preparation of Intermediate Example 22, sebacic acid was used to prepare SIAIS074019 (white solid, 0.96 g, 66% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H), 7.39-7.36 (m, 1H), 7.35 (s, 4H), 7.01 (d, J=9.0 Hz, 1H), 5.80 (s, 1H), 4.68-4.52 (m, 4H), 4.29 (dd, J=15.2, 5.0 Hz, 1H), 4.12 (d, J=11.2 Hz, 1H), 3.72-3.62 (m, 1H), 2.51 (s, 3H), 2.41-2.33 (m, 1H), 2.32-2.23 (m, 2H), 2.23-2.11 (m, 3H), 1.65-1.48 (m, 4H), 1.32-1.21 (m, 8H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₇N₄O₆S⁺ [M+H]⁺: 615.3211; found, 615.4391.

Intermediate Example 29: Synthesis of 11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (SIAIS074020)

According to the procedures for the preparation of Intermediate Example 22, 1,11-undecanedioic acid was used to prepare SIAIS074020 (white solid, 1 g, 67% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 7.39-7.32 (m, 4H), 7.30 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.52 (br, 1H), 4.69-4.59 (m, 3H), 4.53 (s, 1H), 4.29 (dd, J=15.2, 5.0 Hz, 1H), 4.14 (d, J=11.3 Hz, 1H), 3.68-3.64 (m, 1H), 2.51 (s, 3H), 2.44-2.40 (m, 1H), 2.29 (t, J=7.1 Hz, 2H), 2.26-2.12 (m, 3H), 1.68-1.48 (m, 4H), 1.30-1.20 (m, 10H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₃H₄₉N₄O₆S⁺ [M+H]⁺, 629.3367; found, 629.4540.

Intermediate Example 30: Synthesis of 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropanoic acid (SIAIS171004)

According to scheme 7, to a solution of diacid (malonic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), lenalidomide (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0° C. The resulting reaction solution was then stirred at room temperature overnight. After lenalidomide was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS171004 as white solid (0.32 g, 24%). ¹H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 10.03 (s, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.62-7.43 (m, 2H), 5.15 (dd, J=13.4, 4.9 Hz, 1H), 4.36 (dd, J=35.5, 17.5 Hz, 2H), 3.42 (s, 2H), 2.95-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.38-2.28 (m, 1H), 2.07-2.01 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M+H]⁺, 346.1034; found, 346.1015.

Intermediate Example 31: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-4-oxobutanoic acid (SIAIS164084)

According to the procedures for the preparation of Intermediate Example 30, succinic acid was used to prepare SIAIS164084 (white solid, 0.11 g, 44% yield). ¹H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 11.02 (s, 1H), 9.86 (s, 1H), 7.81 (dd, J=7.1, 1.7 Hz, 1H), 7.57-7.40 (m, 2H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.35 (dd, J=35.5, 17.5 Hz, 2H), 2.96-2.87 (m, 1H), 2.65-2.58 (m, 3H), 2.55-2.53 (m, 2H), 2.37-2.29 (m, 1H), 2.06-2.00 (m, 1H). HRMS (ESI) calcd for C₁₇H₁₈N₃O₆ ⁺ [M+H]⁺, 360.1190; found, 360.1198.

Intermediate Example 32: Synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-5-oxopentanoic acid (SIAIS171005)

According to the procedures for the preparation of Intermediate Example 30, glutaric acid was used to prepare SIAIS171005 (white solid, 0.52 g, 35% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 9.80 (s, 1H), 7.81 (d, J=5.8 Hz, 1H), 7.54-7.46 (m, 2H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.36 (dd, J=35.5, 17.5 Hz, 2H), 2.97-2.85 (m, 1H), 2.77-2.75 (m, 2H), 2.66-2.57 (m, 1H), 2.42-2.39 (m, 1H), 2.35 (dd, J=13.1, 4.4 Hz, 1H), 2.30-2.27 (m, 1H), 2.03-1.97 (m, 1H), 1.85-1.79 (m, 2H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M+H]⁺, 374.1347; found, 374.1526.

Intermediate Example 33: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-6-oxohexanoic acid (SIAIS164101)

According to the procedures for the preparation of Intermediate Example 30, adipic acid was used to prepare SIAIS164101 (white solid, 0.4 g, 27% yield). ¹H NMR (500 MHz, MeOD) δ 7.70 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 5.16 (dd, J=13.4, 5.2 Hz, 1H), 4.53-4.43 (m, 2H), 2.95-2.87 (m, 1H), 2.81-2.76 (m, 1H), 2.55-2.48 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.0 Hz, 2H), 2.22-2.16 (m, 1H), 1.79-1.66 (m, 4H). HRMS (ESI) calcd for C₁₉H₂₂N₃O₆ ⁺ [M+H]⁺, 388.1503; found, 388.1714.

Intermediate Example 34: Synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-7-oxoheptanoic acid (SIAIS164102)

According to the procedures for the preparation of Intermediate Example 30, pimelic acid was used to prepare SIAIS164102 (white solid, 0.45 g, 28% yield). ¹H NMR (500 MHz, MeOD) δ 7.70 (d, J=7.9 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 5.16 (dd, J=13.4, 5.2 Hz, 1H), 4.49 (t, J=10.1 Hz, 2H), 2.94-2.87 (m, 1H), 2.81-2.76 (m, 1H), 2.54-2.48 (m, 1H), 2.45 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.0 Hz, 2H), 2.22-2.16 (m, 1H), 1.77-1.72 (m, 2H), 1.70-1.63 (m, 2H), 1.48-1.42 (m, 2H). HRMS (ESI) calcd for C₂₀H₂₄N₃O₆ ⁺ [M+H]⁺, 402.1660; found, 402.1890.

Intermediate Example 35: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid (SIAIS1204057)

According to scheme 8, to a solution of lenalidomide (2 mmol, 1 equiv) in NMP (8 mL) was added tert-butyl 2-bromoacetate (2.4 mmol, 1.2 equiv) and DIPEA (6 mmol, 3 equiv), then stirred at 110° C. overnight. After cooling to room temperature, the resulting solution was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired tert-butyl ester intermediate. This intermediate was treated with TFA (2 mL) in DCM (6 mL) for 1 h at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS1204057 was obtained as yellow solid, 1.0 g, 48%. ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.94 (s, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.26 (d, J=17.0 Hz, 1H), 4.16 (d, J=17.0 Hz, 1H), 3.92 (s, 2H), 2.98-2.85 (m, 1H), 2.62 (d, J=17.3 Hz, 1H), 2.39-2.26 (m, 1H), 2.08-1.99 (m, 1H). HRMS (ESI) calcd for C₁₅H₁₆N₃O₅ ⁺ [M+H]⁺, 318.1084; found, 318.1098.

Intermediate Example 36: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoic acid (SIAIS1204085)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 4-bromobutanoate was used to prepare SIAIS1204085 (yellow solid, 215 mg, 62% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.23 (d, J=17.0 Hz, 1H), 4.13 (d, J=17.0 Hz, 1H), 4.01 (s, 1H), 3.14 (t, J=7.0 Hz, 2H), 2.98-2.86 (m, 1H), 2.66-2.58 (d, J=17.6 Hz, 1H), 2.34 (t, J=7.3 Hz, 2H), 2.32-2.24 (m, 1H), 2.08-1.98 (m, 1H), 1.85-1.75 (m, 2H). HRMS (ESI) calcd for C₁₇H₂₀N₃O₅ ⁺ [M+H]⁺, 346.1379; found, 346.1414.

Intermediate Example 37: Synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid (SIAIS1210133)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 5-bromopentanoate was used to prepare SIAIS1210133 (yellow solid, 215 mg, 60% yield). ¹H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.92 (t, J=10.9 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 5.07 (s, 1H), 4.23 (d, J=17.2 Hz, 1H), 4.13 (d, J=17.1 Hz, 1H), 3.13 (d, J=6.4 Hz, 2H), 2.97-2.87 (m, 1H), 2.61 (d, J=16.7 Hz, 1H), 2.38-2.21 (m, 3H), 2.06-1.98 (m, 1H), 1.67-1.55 (m, 4H). HRMS (ESI) calcd for C₁₅H₂₂N₃O₅ ⁺ [M+H]⁺, 360.1554; found, 360.1551.

Intermediate Example 38: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoic acid (SIAIS1204061)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 6-bromohexanoate was used to prepare SIAIS1204061 (yellow solid, 268 mg, 72% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 6.94 (d, J=7.4 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.24 (d, J=17.0 Hz, 1H), 4.14 (d, J=17.0 Hz, 1H), 4.05 (s, 1H), 3.12 (t, J=7.0 Hz, 2H), 2.98-2.87 (m, 1H), 2.66-2.58 (m, 1H), 2.35-2.25 (m, 1H), 2.22 (t, J=7.0 Hz, 2H), 2.07-2.00 (m, 1H), 1.63-1.50 (m, 4H), 1.43-1.37 (m, 2H). HRMS (ESI) calcd for C₁₉H₂₄N₃O₅ ⁺ [M+H]⁺, 374.1710; found, 374.1720.

Intermediate Example 39: Synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoic acid (SIAIS1204063)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 7-bromoheptanoate was used to prepare SIAIS1204063 (yellow solid, 252 mg, 65% yield). ¹H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.2, 5.0 Hz, 1H), 4.23 (d, J=17.0 Hz, 1H), 4.13 (d, J=17.0 Hz, 1H), 3.11 (t, J=7.0 Hz, 2H), 2.98-2.84 (m, 1H), 2.67-2.57 (m, 1H), 2.35-2.25 (m, 1H), 2.20 (t, J=7.3 Hz, 2H), 2.07-1.99 (m, 1H), 1.63-1.46 (m, 4H), 1.42-1.27 (m, 4H). HRMS (ESI) calcd for C₂₀H₂₆N₃O₅ ⁺ [M+H]⁺, 388.1867; found, 388.1878.

Intermediate Example 40: Synthesis of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione (SIAIS151103)

According to Scheme 9, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (7.2 mmol, 1 equiv),

(8.1 mmol, 1.2 equiv) and DIPEA (36.4 mmol, 5 equiv) in NMP (10 mL) was stirred in a microwave tube for 10 min at room temperature, then charged with argon and heated to 110° C. in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with EA (4×50 mL), the combined organic phase was washed with water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent (v/v): hexanes/EA=1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151103 was obtained as yellow solid (1.1 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 8.36 (s, 2H), 7.64-7.58 (m, 1H), 7.18 (t, J=6.2 Hz, 1H), 7.07 (d, J=7.1 Hz, 1H), 6.84 (t, J=6.2 Hz, 1H), 5.06 (dd, J=12.7, 5.4 Hz, 1H), 3.56 (dd, J=12.2, 6.0 Hz, 2H), 2.96 (t, J=6.1 Hz, 2H), 2.93-2.85 (m, 1H), 2.61-2.51 (m, 2H), 2.06-2.00 (m, 1H). HRMS (ESI) calcd for C₁₅H₁₇N₄O₄ ⁺ [M+H]⁺, 317.1244; found, 317.1236.

Intermediate Example 41: Synthesis of 4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutanoic acid (SIAIS164119)

According to scheme 10, to a solution of succinic acid (295.2 mg, 2.5 mmol, 2.5 equiv) in anhydrous DMF (5 mL) and anhydrous DCM (50 mL) was added NMM (1.01 g, 10.0 mmol, 10 equiv), SIAIS151103 (316.3 mg, 1 mmol, 1 equiv), HOAt (163.3 mg, 1.2 mmol, 1.2 equiv) and EDCI (230 mg, 1.2 mmol, 1.2 equiv) at 0° C. The resulting reaction solution was stirred at 0° C. for 5 h and then at room temperature overnight. After the reaction was complete, the resulting solution was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v) acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS164119 as yellow solid (170 mg, 41%). ¹H NMR (500 MHz, MeOD) δ 7.55-7.50 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.04 (t, J=6.3 Hz, 1H), 5.05 (dd, J=12.4, 5.5 Hz, 1H), 3.47-3.39 (m, 4H), 2.89-2.82 (m, 1H), 2.79-2.65 (m, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.16-2.05 (m, 1H). HRMS (ESI) calcd for C₁₉H₂₁N₄O₇ ⁺ [M+H]⁺, 417.1405; found, 417.0916.

Intermediate Example 42: Synthesis of (2S,4R)-1-((S)-2-(4-azidobutyrylamino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (SIAIS164050)

According to scheme 11, to a solution of VHL-1 (934 mg, 2 mmol, 1 equiv) and 4-azidobutanoic acid (258.2 mg, 2 mmol, 1 equiv) in DMF (5 mL) and DCM (20 mL) was added HOAt (54.4 mg, 0.4 mmol, 0.2 equiv), EDCI (766.8 mg, 4 mmol, 2 equiv) and NMM (2.02 g, 20 mmol, 10 equiv) at room temperature. The resulting reaction solution was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the resulting solution was concentrated under reduced pressure, the residue was poured into 90% saline, extracted with EA (4×50 mL), the combined organic phase was washed with water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent (v/v): DCM/MeOH=40:1) to give the desired product SIAIS164050 as pale yellow liquid (734 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.87 (s, 1H), 7.48-7.41 (m, 4H), 4.62 (s, 1H), 4.58-4.50 (m, 3H), 4.38-4.33 (m, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.80 (dd, J=10.9, 3.9 Hz, 1H), 3.33 (t, J=5.0 Hz, 2H), 2.48 (d, J=5.3 Hz, 3H), 2.41-2.32 (m, 2H), 2.22 (dd, J=13.1, 7.6 Hz, 1H), 2.11-2.06 (m, 1H), 1.90-1.82 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₂₆H₃₆N₇O₄S⁺ [M+H]⁺, 542.2544; found, 542.2256.

Intermediate Example 43: Synthesis of 4-(1-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-4-yl)butanoic acid (SIAIS164128)

According to scheme 12, to a solution of 5-hexynoic acid (22.4 mg, 0.2 mmol, 1 equiv) and SIAIS164050 (108.3 mg, 0.2 mmol, 1 equiv) in DMF (1 mL), tBuOH (1 mL) and water (1 mL) was added CuSO₄ (31.9 mg, 0.2 mmol, 1 equiv) and sodium ascorbate (39.6 mg, 0.2 mmol, 1 equiv) at room temperature. The resulting reaction solution was stirred at room temperature for 2 h. After the reaction was complete detected by LC-MS, the resulting solution was purified by reverse-phase chromatography (eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%), to yield the desired product SIAIS164128 as white solid (100 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 9.19 (d, J=3.4 Hz, 1H), 7.87 (s, 1H), 7.51-7.42 (m, 4H), 4.60 (s, 1H), 4.59-4.54 (m, 2H), 4.51 (s, 1H), 4.43 (t, J=6.8 Hz, 2H), 4.36 (d, J=15.3 Hz, 1H), 3.93 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.8 Hz, 1H), 2.77 (t, J=7.6 Hz, 2H), 2.51 (d, J=3.8 Hz, 3H), 2.36 (t, J=7.3 Hz, 2H), 2.32-2.28 (m, 2H), 2.25-2.15 (m, 3H), 2.11-2.06 (m, 1H), 2.00-1.94 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₄N₇O₆S⁺ [M+H]⁺, 654.3068; found, 654.2990.

Intermediate Example 44: Synthesis of 11-(((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (SIAIS219048)

According to scheme 13, to a solution of diacid (1,11-undecanedioic acid, 0.25 mmol, 2.5 equiv) in anhydrous DMF (4 mL) and anhydrous DCM (10 mL) was added NMM (0.5 mmol, 5 equiv), trans-VHL-1 (0.1 mmol, 1 equiv), HOAt (0.15 mmol, 1.5 equiv) and EDCI (0.15 mmol, 1.5 equiv) at 0° C. The resulting reaction solution was stirred at 0° C. for 2 h and then at room temperature overnight. After trans-VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS219048 as white solid (48 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 8.78 (s, 1H), 7.38-7.31 (m, 4H), 7.31-7.28 (m, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.50 (br, 1H), 4.67-4.56 (m, 3H), 4.51 (s, 1H), 4.26 (dd, J=15.2, 5.0 Hz, 1H), 4.13 (d, J=11.3 Hz, 1H), 3.64-3.62 (m, 1H), 2.50 (s, 3H), 2.43-2.40 (m, 1H), 2.27 (t, J=7.1 Hz, 2H), 2.25-2.11 (m, 3H), 1.67-1.46 (m, 4H), 1.30-1.21 (m, 10H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₃H₄₉N₄O₆S⁺ [M+H]⁺, 629.3367; found, 629.3377.

Intermediate Example 45: Synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) propionic acid (SIAIS172147) Synthesis of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (SIAIS172136)

According to scheme 14, 4-bromoisobenzofuran-1,3-dione (500 mg, 2.20 mmol), 3-aminopiperidine-2,6-dione (400 mg, 2.42 mmol) and anhydrous sodium acetate was added in a 100 mL egg-shaped flask, followed by glacial acetic acid (10 mL). The resulting reaction solution was slowly heated to 140° C. and stirred for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature, a large amount of white solid was precipitated. After filtration, the filter cake, water (10 mL) and methanol (2 mL) were added to a flask and stirred for 0.5 h. After filtration, the filter cake was washed with water, concentrated under reduced pressure to yield the desired product SIAIS172136 as white solid (700 mg, 94%). ¹H NMR (500 MHz, DMSO) δ 11.14 (s, 1H), 8.14 (d, J=1.4 Hz, 1H), 8.09 (dd, J=7.9, 1.7 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 5.16 (dd, J=12.9, 5.4 Hz, 1H), 2.93-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.08-2.04 (m, 1H). HRMS (ESI) calcd for C₁₃H₁₀BrN₂O₄ ⁺ [M+H]⁺, 336.9818; found, 336.9810.

Synthesis of tert-butyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acrylate (SIAIS172145)

According to scheme 14, tri-tert-butylphosphine tetrafluoroborate (110 mg, 0.38 mmol), N-methyldicyclohexylamine (250 mg, 1.28 mmol), Pd₂(dba)₃(163 mg, 0.64 mmol) and anhydrous dioxane was added in a 50 mL egg-shaped flask and stirred at room temperature for 30 min, then SIAIS172136 (300 mg, 0.89 mmol) and tert-butyl acrylate were added. The resulting reaction solution was slowly heated to 55° C. under an atmosphere of nitrogen and stirred for 12 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (eluent (v/v): EA/PE=2:3) to yield the desired product SIAIS172145 as light yellow solid (270 mg, 79%). ¹H NMR (500 MHz, CDCl₃) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.84 (dd, J=7.8, 1.2 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 6.54 (d, J=16.0 Hz, 1H), 5.00 (dd, J=12.5, 5.3 Hz, 1H), 2.94-2.72 (m, 3H), 2.20-2.13 (m, 1H), 1.54 (s, 9H). HRMS (ESI) calcd for C₂₀H₂₁N₂O₆ ⁺ [M+H]⁺, 385.1394; found, 385.1389.

Synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) propionic acid (SIAIS172147)

According to scheme 14, SIAIS172145 (250 mg, 0.65 mmol) was added in a 100 mL egg-shaped flask, followed by dioxane (20 mL) anad 10% wet Pd/C. After extracting and recharging with H₂ (25 psi) 3 times, the reaction solution was allowed to stir at RT overnight. After the reaction was complete, the reaction solution was filtrated, washed with dioxane, the filtrate was concentrated under reduced pressure to give a light yellow oil, the crude was used for the following reaction without further purification. The crude, TFA (1 mL) and anhydrous DCM were added in a 50 mL egg-shaped flask, and stirred at RT for 2 h, when the reaction was complete, the resulting solution was concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1% TFA)=10%-100%, to yield the desired product SIAIS172147 after concentration and freeze-drying, (white solid, 180 mg, 84% over 2 steps). ¹H NMR (500 MHz, DMSO) δ 12.22 (s, 1H), 11.12 (s, 1H), 7.86-7.79 (m, 2H), 7.77-7.70 (m, 1H), 5.13 (dd, J=12.8, 5.4 Hz, 1H), 3.01 (t, J=7.4 Hz, 2H), 2.93-2.85 (m, 1H), 2.64 (t, J=7.4 Hz, 2H), 2.62-2.50 (m, 2H), 2.08-2.02 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₅N₂O₆ ⁺ [M+H]⁺, 331.0925; found, 331.0919.

COMPOUND EXAMPLES Compound Example 1: Synthesis of 4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197065)

According to scheme 15, to a stirred solution of corresponding ALK inhibitor (Brigatinib Analogue A, 0.02 mmol, 1 equiv) and intermediate LM (SIAIS151001, 0.02 mmol, 1 equiv), in DMF (1 mL) and DCM (5 mL) was added HOAt (0.04 mmol, 2 equiv), EDCI (0.04 mmol, 2 equiv) and NMM (0.2 mmol, 10 equiv) sequentially at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the resulting solution was purified by preparative HPLC, eluent (v/v): acetonitrile/(water+0.05% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1197065 was obtained as yellow solid (16.2 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.05 (s, 1H), 7.65 (dd, J=13.8, 7.7 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J=8.4, 7.2 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.1 Hz, 1H), 6.65 (s, 1H), 6.46 (d, J=7.9 Hz, 1H), 4.97 (dd, J=12.4, 5.4 Hz, 1H), 3.84 (t, J=5.8 Hz, 4H), 3.80 (s, 3H), 3.72 (t, J=5.0 Hz, 4H), 3.48 (t, J=5.0 Hz, 2H), 3.20 (s, 4H), 2.80-2.68 (m, 3H), 2.66-2.58 (m, 2H), 2.04-1.96 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₈P⁺ [M+H]⁺, 858.2890; found, 858.3506.

Compound Example 2: Synthesis of 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197067)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151004) was used to prepare SIAIS1197067 (yellow solid, 16.7 mg, 62% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=13.9, 7.7 Hz, 1H), 7.55 (s, 1H), 7.50 (dd, J=8.5, 7.2 Hz, 1H), 7.37 (t, J=7.0 Hz, 1H), 7.28 (d, J=6.7 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 6.68 (s, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.02 (dd, J=12.5, 5.5 Hz, 1H), 3.82 (s, 3H), 3.79 (t, J=6.1 Hz, 2H), 3.74 (d, J=4.2 Hz, 4H), 3.68 (t, J=5.3 Hz, 2H), 3.66-3.59 (m, 4H), 3.43 (t, J=5.2 Hz, 2H), 3.28-3.18 (m, 4H), 2.86-2.76 (m, 1H), 2.75-2.61 (m, 4H), 2.11-2.03 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₉P⁺ [M+H]⁺, 902.3152; found, 902.3791.

Compound Example 3: Synthesis of 4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy) ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197069)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151005) was used to prepare SIAIS1197069 (yellow solid, 13.7 mg, 51% yield). ¹H NMR (500 MHz, MeOD) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J=14.0, 7.7 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.70 (s, 1H), 6.56 (s, 1H), 5.02 (dd, J=12.6, 5.5 Hz, 1H), 3.83 (s, 3H), 3.80-3.71 (m, 6H), 3.68-3.57 (m, 10H), 3.44 (t, J=5.0 Hz, 2H), 3.28 (s, 2H), 3.23 (s, 2H), 2.87-2.78 (m, 1H), 2.75-2.62 (m, 4H), 2.12-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₄ClN₉O₁₀P⁺ [M+H]⁺, 946.3961; found, 946.1771.

Compound Example 4: Synthesis of 4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197071)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151006) was used to prepare SIAIS1197071 (yellow solid, 4.8 mg, 18% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J=15.0, 7.4 Hz, 1H), 7.58-7.49 (m, 2H), 7.37 (t, J=8.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.07-7.00 (m, 2H), 6.72 (s, 1H), 6.56 (s, 1H), 5.02 (dd, J=12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.80-3.73 (m, 6H), 3.64-3.55 (m, 14H), 3.46 (t, J=5.5 Hz, 2H), 3.24 (s, 4H), 2.87-2.78 (m, 1H), 2.74-2.67 (m, 4H), 2.10-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₇H₅₈ClN₉O₁₁P⁺ [M+H]⁺, 990.3676; found, 990.4374.

Compound Example 5: Synthesis of 4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197073)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151007) was used to prepare SIAIS1197073 (yellow solid, 4.5 mg, 17% yield). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J=14.0, 7.5 Hz, 1H), 7.59-7.48 (m, 2H), 7.38 (t, J=7.1 Hz, 1H), 7.29 (s, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.73 (s, 1H), 6.57 (s, 1H), 5.02 (dd, J=12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.80-3.72 (m, 6H), 3.71-3.54 (m, 18H), 3.46 (t, J=5.5 Hz, 2H), 3.24 (s, 4H), 2.86-2.77 (m, 1H), 2.76-2.62 (m, 4H), 2.11-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₉H₆₂ClN₉O₁₂P⁺ [M+H]⁺, 1034.3939; found, 1034.3055.

Compound Example 6: Synthesis of 4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197055)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151025) was used to prepare SIAIS1197055 (yellow solid, 18.8 mg, 69% yield). ¹H NMR (500 MHz, DMSO) δ 11.12 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.64 (dd, J=8.4, 7.2 Hz, 1H), 7.59-7.54 (m, 1H), 7.43 (d, J=9.4 Hz, 1H), 7.39 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.09 (d, J=7.1 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.55 (dd, J=8.5, 2.2 Hz, 1H), 5.08 (dd, J=12.9, 5.1 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 4H), 3.28 (s, 2H), 3.20 (s, 4H), 1.78 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₃₈H₄₀ClN₉O₇P⁺ [M+H]⁺, 800.2471; found, 800.2478.

Compound Example 7: Synthesis of 4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197057)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151026) was used to prepare SIAIS1197057 (yellow solid, 13.5 mg, 50% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=14.0, 7.6 Hz, 1H), 7.58 (t, J=7.8 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J=7.5 Hz, 1H), 4.99 (dd, J=12.8, 5.5 Hz, 1H), 3.83 (s, 3H), 3.78-3.68 (m, 6H), 3.18 (s, 4H), 2.84-2.74 (m, 3H), 2.71-2.59 (m, 2H), 2.02-1.94 (m, 1H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₃₉H₄₂ClN₉O₇P⁺ [M+H]⁺, 814.2628; found, 814.3219.

Compound Example 8: Synthesis of 4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197059)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151019) was used to prepare SIAIS1197059 (yellow solid, 14.4 mg, 53% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=13.8, 7.3 Hz, 1H), 7.54 (dd, J=8.5, 7.1 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.69 (s, 1H), 6.54 (d, J=7.5 Hz, 1H), 5.03 (dd, J=12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.78-3.65 (m, 4H), 3.44 (t, J=6.6 Hz, 2H), 3.18 (s, 4H), 2.89-2.77 (m, 1H), 2.75-2.63 (m, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.11-2.04 (m, 1H), 2.04-1.97 (m, 2H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₀H₄₄ClN₉O₇P⁺ [M+H]⁺, 828.2784; found, 828.2783.

Compound Example 9: Synthesis of 4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197061)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151020) was used to prepare SIAIS1197061 (yellow solid, 12.6 mg, 45% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.64 (dd, J=14.1, 7.8 Hz, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.41-7.30 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.69 (s, 1H), 6.53 (s, 1H), 5.00 (dd, J=12.6, 5.5 Hz, 1H), 3.85 (s, 3H), 3.78-3.66 (m, 4H), 3.39 (t, J=5.6 Hz, 2H), 3.19 (s, 4H), 2.85-2.74 (m, 1H), 2.73-2.60 (m, 2H), 2.53 (t, J=6.6 Hz, 2H), 2.07-2.00 (m, 1H), 1.87 (d, J=13.5 Hz, 6H), 1.81-1.71 (m, 4H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₇P⁺ [M+H]⁺, 842.2941; found, 842.2951.

Compound Example 10: Synthesis of 4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197063)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151027) was used to prepare SIAIS1197063 (yellow solid, 15.6 mg, 58% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=13.5, 7.0 Hz, 1H), 7.53 (dd, J=8.6, 7.1 Hz, 2H), 7.36 (t, J=6.8 Hz, 1H), 7.32 (d, J=6.8 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.00 (d, J=6.9 Hz, 1H), 6.71 (s, 1H), 6.55 (d, J=7.7 Hz, 1H), 5.01 (dd, J=12.5, 5.4 Hz, 1H), 3.85 (s, 3H), 3.78-3.68 (m, 4H), 3.36 (t, J=6.8 Hz, 2H), 3.22 (s, 4H), 2.86-2.74 (m, 1H), 2.74-2.62 (m, 2H), 2.49 (t, J=7.4 Hz, 2H), 2.10-2.03 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.76-1.66 (m, 4H), 1.54-1.46 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺, 856.3097; found, 856.3109.

Compound Example 11: Synthesis of 4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197077)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151086) was used to prepare SIAIS1197077 (yellow solid, 17.6 mg, 65% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=13.8, 7.7 Hz, 1H), 7.53 (dd, J=8.6, 7.1 Hz, 2H), 7.37 (t, J=7.1 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.72 (s, 1H), 6.56 (d, J=8.5 Hz, 1H), 5.03 (dd, J=12.5, 5.5 Hz, 1H), 3.85 (s, 3H), 3.79-3.67 (m, 4H), 3.34 (t, J=6.9 Hz, 2H), 3.24 (d, J=14.7 Hz, 4H), 2.87-2.77 (m, 1H), 2.75-2.64 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 2.12-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.74-1.62 (m, 4H), 1.54-1.40 (m, 4H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₇P⁺ [M+H]⁺, 870.3254; found, 870.3009.

Compound Example 12: Synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197087)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151010) was used to prepare SIAIS1197087 (white solid, 15.7 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 8.85 (s, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.65 (dd, J=14.1, 7.4 Hz, 1H), 7.54 (s, 1H), 7.44-7.32 (m, 5H), 6.69 (s, 1H), 6.55 (s, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.60-4.44 (m, 2H), 4.50 (s, 1H), 4.41-4.31 (m, 3H), 4.07 (d, J=10.4 Hz, 2H), 3.87 (d, J=9.8 Hz, 1H), 3.83 (s, 3H), 3.80-3.64 (m, 9H), 3.25 (s, 4H), 2.44 (s, 3H), 2.27-2.17 (m, 1H), 2.13-2.04 (m, 1H), 1.87 (d, J=13.5 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₉PS⁺ [M+H]⁺, 1059.4077; found, 1059.4091.

Compound Example 13: Synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197079)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151002) was used to prepare SIAIS1197079 (white solid, 14.9 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J=14.0, 7.7 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.42-7.33 (m, 3H), 7.29 (d, J=7.8 Hz, 1H), 6.72 (s, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.64 (s, 1H), 4.60-4.52 (m, 2H), 4.49 (s, 1H), 4.34 (d, J=15.5 Hz, 1H), 3.88 (d, J=10.9 Hz, 1H), 3.84 (s, 3H), 3.81-3.66 (m, 9H), 3.62-3.58 (m, 4H), 3.31 (s, 2H), 3.21 (s, 2H), 2.77-2.66 (m, 2H), 2.46 (s, 3H), 2.51-2.43 (m, 1H), 2.43-2.36 (m, 1H), 2.25-2.18 (m, 1H), 2.12-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₉PS⁺ [M+H]⁺, 1087.4390; found, 1087.3478.

Compound Example 14: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197081)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151003) was used to prepare SIAIS1197081 (white solid, 17.1 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=14.1, 7.8 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.44-7.35 (m, 3H), 7.29 (d, J=8.2 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 4.64 (s, 1H), 4.59-4.51 (m, 2H), 4.49 (s, 1H), 4.35 (d, J=15.5 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.85 (s, 3H), 3.82-3.73 (m, 7H), 3.72-3.65 (m, 2H), 3.63-3.54 (m, 8H), 3.44 (t, J=7.0 Hz, 1H), 3.31 (s, 2H), 3.24 (s, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.60-2.50 (m, 1H), 2.47 (s, 3H), 2.49-2.40 (m, 1H), 2.25-2.18 (m, 1H), 2.11-2.05 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₁₀PS⁺ [M+H]⁺, 1131.4652; found, 1131.4651.

Compound Example 15: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197083)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151008) was used to prepare SIAIS1197083 (white solid, 16.7 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J=13.5, 8.1 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.42-7.35 (m, 3H), 7.31 (d, J=8.6 Hz, 1H), 6.73 (s, 1H), 6.58 (d, J=7.5 Hz, 1H), 4.64 (s, 1H), 4.59-4.50 (m, 2H), 4.49 (s, 1H), 4.35 (d, J=15.5 Hz, 1H), 3.87 (d, J=12.2 Hz, 1H), 3.85 (s, 3H), 3.82-3.72 (m, 7H), 3.73-3.65 (m, 2H), 3.64-3.53 (m, 12H), 3.31 (s, 2H), 3.24 (s, 2H), 2.72 (t, J=6.2 Hz, 2H), 2.59-2.51 (m, 1H), 2.46 (s, 3H), 2.49-2.40 (m, 1H), 2.25-2.16 (m, 1H), 2.11-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₁₁PS⁺ [M+H]⁺, 1175.4915; found, 1175.4981.

Compound Example 16: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197085)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151009) was used to prepare SIAIS1197085 (white solid, 16.5 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.67 (dd, J=14.0, 6.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.44-7.34 (m, 3H), 7.30 (d, J=8.5 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J=8.1 Hz, 1H), 4.64 (s, 1H), 4.59-4.51 (m, 2H), 4.49 (s, 1H), 4.35 (d, J=15.6 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.85 (s, 3H), 3.82-3.4 (m, 7H), 3.74-3.67 (m, 2H), 3.65-3.54 (m, 16H), 3.31 (s, 2H), 3.25 (s, 2H), 2.72 (t, J=6.1 Hz, 2H), 2.60-2.51 (m, 1H), 2.47 (s, 3H), 2.50-2.40 (m, 1H), 2.25-2.17 (m, 1H), 2.11-2.04 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₉H₈₁ClN₁₀O₁₂PS⁺ [M+H]⁺, 1219.5177; found, 1219.5229.

Compound Example 17: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197145)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074011) was used to prepare SIAIS1197145 (white solid, 10.1 mg, 37%). ¹H NMR (500 MHz, MeOD) δ 9.98 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.80-7.45 (m, 8H), 7.39 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 4.66-4.35 (m, 5H), 4.05 (s, 4H), 3.96 (s, 3H), 3.89 (d, J=10.7 Hz, 1H), 3.80 (d, J=8.1 Hz, 1H), 3.70 (s, 2H), 3.61 (s, 2H), 2.91-2.63 (m, 4H), 2.61 (s, 3H), 2.23 (s, 1H), 2.07 (s, 1H), 1.87 (d, J=13.4 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₄₉H₆₁ClN₁₀O₇PS⁺ [M+H]⁺, 999.3866; found, 999.1918.

Compound Example 18: Synthesis of (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197147)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074012) was used to prepare SIAIS1197147 (white solid, 9.4 mg, 35%). ¹H NMR (500 MHz, MeOD) δ 10.00 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.79-7.63 (m, 3H), 7.61-7.46 (m, 6H), 7.22 (d, J=8.6 Hz, 1H), 4.65-4.47 (m, 4H), 4.41 (d, J=15.7 Hz, 1H), 4.07 (s, 4H), 3.97 (s, 3H), 3.93 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.6 Hz, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.60 (s, 3H), 2.53 (t, J=7.4 Hz, 2H), 2.40 (t, J=7.1 Hz, 2H), 2.28-2.20 (m, 1H), 2.11-2.02 (m, 1H), 2.01-1.92 (m, 2H), 1.87 (d, J=13.6 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₇PS⁺ [M+H]⁺, 1013.4023; found, 1013.2012.

Compound Example 19: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197149)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074013) was used to prepare SIAIS1197149 (white solid, 11.4 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 10.02 (d, J=2.9 Hz, 1H), 8.26 (s, 1H), 8.13 (m, 1H), 7.80-7.63 (m, 3H), 7.60-7.49 (m, 6H), 7.25 (d, J=8.8 Hz, 1H), 4.64-4.46 (m, 4H), 4.40 (dd, J=15.7, 3.7 Hz, 1H), 4.10 (s, 4H), 3.97 (s, 3H), 3.90 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.9 Hz, 1H), 3.76 (s, 2H), 3.68 (s, 2H), 2.61 (s, 3H), 2.59-2.48 (m, 2H), 2.38-2.32 (m, 2H), 2.27-2.21 (m, 1H), 2.10-2.03 (m, 1H), 1.87 (d, J=13.6 Hz, 6H), 1.77-1.64 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₇PS⁺ [M+H]⁺, 1027.4179; found, 1027.2037.

Compound Example 20: Synthesis of (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197151)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074014) was used to prepare SIAIS1197151 (white solid, 12.7 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 10.03 (d, J=1.2 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.78-7.65 (m, 3H), 7.61-7.48 (m, 6H), 7.25 (d, J=8.6 Hz, 1H), 4.63 (d, J=7.6 Hz, 1H), 4.59-4.53 (m, 2H), 4.50 (s, 1H), 4.40 (dd, J=15.8, 6.4 Hz, 1H), 4.11 (s, 4H), 3.98 (s, 3H), 3.90 (d, J=11.0 Hz, 1H), 3.80 (dd, J=11.0, 3.7 Hz, 1H), 3.77-3.60 (m, 4H), 2.61 (s, 3H), 2.52 (t, J=7.5 Hz, 2H), 2.36-2.19 (m, 3H), 2.12-2.04 (m, 1H), 1.87 (d, J=13.6 Hz, 6H), 1.72-1.57 (m, 4H), 1.47-1.29 (m, 2H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₇PS⁺ [M+H]⁺, 1041.4336; found, 1041.2125.

Compound Example 21: Synthesis of (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074015) was used to prepare SIAIS1197153 (white solid, 6.8 mg, 25%). ¹H NMR (500 MHz, MeOD) δ 9.99 (d, J=4.4 Hz, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.74 (dd, J=13.0, 7.6 Hz, 1H), 7.66 (t, J=7.5 Hz, 2H), 7.60-7.46 (m, 5H), 7.40 (s, 1H), 7.14 (d, J=8.7 Hz, 1H), 4.63 (d, J=6.1 Hz, 1H), 4.60-4.52 (m, 2H), 4.50 (s, 1H), 4.40 (dd, J=15.8, 7.7 Hz, 1H), 4.05 (s, 4H), 3.96 (s, 3H), 3.91 (d, J=11.0 Hz, 1H), 3.80 (dd, J=11.1, 3.7 Hz, 1H), 3.68 (s, 2H), 3.62 (s, 2H), 2.61 (s, 3H), 2.51 (t, J=7.5 Hz, 2H), 2.40-2.17 (m, 3H), 2.11-2.03 (m, 1H), 1.87 (d, J=13.5 Hz, 6H), 1.70-1.55 (m, 4H), 1.45-1.30 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₇PS⁺ [M+H]⁺, 1055.4492; found, 1055.2208.

Compound Example 22: Synthesis of (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197155)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074016) was used to prepare SIAIS1197155 (white solid, 8.3 mg, 31%). ¹H NMR (500 MHz, MeOD) δ 9.96 (s, 1H), 8.19 (d, J=14.1 Hz, 2H), 7.73 (dd, J=14.0, 6.8 Hz, 1H), 7.67-7.45 (m, 6H), 7.31 (s, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.64 (s, 1H), 4.60-4.52 (m, 2H), 4.50 (s, 1H), 4.41 (d, J=15.8 Hz, 1H), 4.00 (s, 4H), 3.95 (s, 3H), 3.91 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.8 Hz, 1H), 3.63 (s, 2H), 3.57 (s, 2H), 2.60 (s, 3H), 2.50 (t, J=7.6 Hz, 2H), 2.37-2.18 (m, 3H), 2.11-2.03 (m, 1H), 1.87 (d, J=13.6 Hz, 6H), 1.70-1.55 (m, 4H), 1.45-1.30 (m, 6H), 1.02 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₇PS⁺ [M+H]⁺, 1069.4649; found, 1069.2386.

Compound Example 23: Synthesis of (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074019) was used to prepare SIAIS1197157 (white solid, 10.6 mg, 39%). ¹H NMR (500 MHz, MeOD) δ 9.56 (d, J=4.2 Hz, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 7.62-7.30 (m, 6H), 6.86 (s, 1H), 6.71 (s, 1H), 4.64 (d, J=3.5 Hz, 1H), 4.60-4.47 (m, 3H), 4.39 (dd, J=15.7, 3.2 Hz, 1H), 4.00-3.69 (m, 9H), 3.36 (s, 4H), 2.55 (d, J=3.8 Hz, 3H), 2.51-2.40 (m, 2H), 2.38-2.18 (m, 3H), 2.12-2.02 (m, 1H), 1.89 (dd, J=13.6, 3.5 Hz, 6H), 1.62 (s, 4H), 1.35 (s, 8H), 1.03 (t, J=5.8 Hz, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₇PS⁺ [M+H]⁺, 1083.4805; found, 1083.2486.

Compound Example 24: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propenamide. (SIAIS151113)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151001) was used to prepare SIAIS151113 (yellow solid, 10.4 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J=8.1, 3.8 Hz, 1H), 8.13 (s, 1H), 7.74-7.67 (m, 2H), 7.63-7.59 (m, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.41-7.31 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 7.00 (d, J=1.9 Hz, 1H), 6.81 (dd, J=8.8, 2.4 Hz, 1H), 5.03 (dd, J=12.5, 5.5 Hz, 1H), 4.10-3.85 (m, 2H), 3.92 (s, 3H), 3.79 (t, J=5.9 Hz, 2H), 3.71 (t, J=5.1 Hz, 2H), 3.68-3.64 (m, 2H), 3.50 (t, J=5.0 Hz, 2H), 2.93-2.61 (m, 4H), 2.48 (t, J=5.9 Hz, 2H), 2.10-2.01 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.83-1.75 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₈P⁺ [M+H]⁺: 872.3047, found, 872.2645.

Compound Example 25: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propenamide. (SIAIS151114)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151004) was used to prepare SIAIS151114 (yellow solid, 9.8 mg, 53%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J=7.5, 3.5 Hz, 1H), 8.13 (s, 1H), 7.72-7.67 (m, 2H), 7.62-7.59 (m, 1H), 7.52 (dd, J=8.5, 7.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.07 (d, J=8.5 Hz, 1H), 7.01 (d, J=6.9 Hz, 1H), 6.99 (s, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.04 (dd, J=12.6, 5.5 Hz, 1H), 4.00-3.94 (m, 1H), 3.90 (s, 3H), 3.76 (t, J=6.1 Hz, 2H), 3.72 (t, J=5.3 Hz, 2H), 3.70-3.62 (m, 8H), 3.48 (t, J=5.3 Hz, 2H), 2.87-2.80 (m, 1H), 2.75-2.67 (m, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.13-2.07 (m, 3H), 1.88 (s, 3H), 1.86 (s, 3H), 1.84-1.77 (m, 2H). HRMS (ESI) calcd for C₄₄H₅₂ClN₉O₉P⁺ [M+H]⁺: 916.3309, found, 916.2857.

Compound Example 26: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propenamide. (SIAIS151115)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151005) was used to prepare SIAIS151115 (yellow solid, 16.8 mg, 87%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73-7.66 (m, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.5, 7.1 Hz, 1H), 7.39 (t, J=7.1 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 7.00 (s, 1H), 6.81 (d, J=6.9 Hz, 1H), 5.04 (dd, J=12.7, 5.5 Hz, 1H), 4.02-3.96 (m, 1H), 3.90 (s, 3H), 3.75-3.67 (m, 7H), 3.65 (s, 3H), 3.64-3.63 (m, 3H), 3.61-3.59 (m, 2H), 3.48 (t, J=5.2 Hz, 2H), 3.38-3.35 (m, 1H), 2.89-2.81 (m, 1H), 2.76-2.67 (m, 2H), 2.45 (t, J=6.0 Hz, 2H), 2.16-2.07 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84-1.78 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₆ClN₉O₁₀P⁺ [M+H]⁺: 960.3571, found, 960.3920.

Compound Example 27: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide. (SIAIS151116)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151006) was used to prepare SIAIS151116 (yellow solid, 13.5 mg, 67%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.75-7.66 (m, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.51 (dd, J=8.5, 7.1 Hz, 1H), 7.38 (dd, J=7.0, 6.0 Hz, 1H), 7.05-6.99 (m, 3H), 6.82 (d, J=8.2 Hz, 1H), 5.03 (dd, J=12.7, 5.5 Hz, 1H), 4.03-3.96 (m, 1H), 3.90 (s, 3H), 3.75-3.68 (m, 6H), 3.65-3.59 (m, 12H), 3.45 (t, J=5.3 Hz, 2H), 3.39-3.34 (m, 2H), 2.88-2.81 (m, 1H), 2.77-2.62 (m, 2H), 2.45 (t, J=6.0 Hz, 2H), 2.16-2.12 (m, 2H), 2.11-2.06 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.85-1.78 (m, 2H). HRMS (ESI) calcd for C₄₈H₆₀ClN₉O₁₁P⁺ [M+H]⁺: 1004.3833, found, 1004.4184.

Compound Example 28: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide. (SIAIS151117)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151007) was used to prepare SIAIS151117 (yellow solid, 15.8 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 8.24 (dd, J=7.5, 3.5 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.69 (ddd, J=13.9, 7.7, 1.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.52 (dd, J=8.5, 7.1 Hz, 1H), 7.42-7.38 (m, 1H), 7.16-7.11 (m, 1H), 7.03 (dd, J=15.1, 7.8 Hz, 2H), 6.92 (d, J=8.7 Hz, 1H), 5.03 (dd, J=12.8, 5.5 Hz, 1H), 4.06-4.00 (m, 1H), 3.92 (s, 3H), 3.75-3.71 (m, 4H), 3.69 (t, J=5.3 Hz, 2H), 3.64-3.60 (m, 16H), 3.53-3.48 (m, 2H), 3.45 (t, J=5.3 Hz, 2H), 2.88-2.80 (m, 1H), 2.75-2.64 (m, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.20-2.17 (m, 2H), 2.11-2.06 (m, 1H), 1.95-1.89 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H). HRMS (ESI) calcd for C₅₀H₆₄ClN₉O₁₂P⁺ [M+H]⁺: 1049.5400, found, 1049.4482.

Compound Example 29: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide. (SIAIS151120)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151025) was used to prepare SIAIS151120 (yellow solid, 11.1 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.31 (dd, J=7.5, 3.5 Hz, 1H), 8.10 (s, 1H), 7.72-7.66 (m, 2H), 7.62-7.57 (m, 2H), 7.40-7.36 (m, 1H), 7.13 (d, J=7.0 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.08 (dd, J=12.6, 5.5 Hz, 1H), 4.07-4.01 (m, 3H), 3.90 (s, 3H), 3.74-3.69 (m, 2H), 3.38-3.31 (m, 2H), 2.88-2.83 (m, 1H), 2.78-2.76 (m, 1H), 2.75-2.71 (m, 1H), 2.15-2.08 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.85-1.78 (m, 2H). HRMS (ESI) calcd for C₃₉H₄₂ClN₉O₇P⁺ [M+H]⁺: 814.2628, found, 814.3211.

Compound Example 30: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propenamide. (SIAIS151121)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151026) was used to prepare SIAIS151121 (yellow solid, 14 mg, 85%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J=7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (ddd, J=13.9, 7.8, 1.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.41-7.36 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.07 (d, J=6.9 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 5.03 (dd, J=12.4, 5.5 Hz, 1H), 4.02-3.96 (m, 1H), 3.92 (s, 3H), 3.71-3.67 (m, 4H), 3.40-3.34 (m, 2H), 2.86-2.79 (m, 1H), 2.75-2.65 (m, 2H), 2.56 (dd, J=6.9, 5.3 Hz, 2H), 2.12-2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.81-1.72 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₄ClN₉O₇P⁺ [M+H]⁺: 828.2784, found, 828.3370.

Compound Example 31: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamide. (SIAIS151118)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151019) was used to prepare SIAIS151118 (yellow solid, 13.2 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.75-7.73 (m, 1H), 7.69 (ddd, J=13.9, 7.7, 1.4 Hz, 1H), 7.62-7.58 (m, 1H), 7.56 (dd, J=9.0, 7.5 Hz, 1H), 7.41-7.36 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.99 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.06 (dd, J=12.6, 5.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.91 (s, 3H), 3.71-3.68 (m, 2H), 3.41 (t, J=6.7 Hz, 2H), 3.37-3.33 (m, 2H), 2.89-2.81 (m, 1H), 2.77-2.69 (m, 2H), 2.34 (t, J=7.0 Hz, 2H), 2.14-2.05 (m, 3H), 2.03-1.97 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.81-1.72 (m, 2H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₇P⁺ [M+H]⁺: 842.2941, found, 842.3294.

Compound Example 32: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide. (SIAIS151119)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151020) was used to prepare SIAIS151119 (yellow solid, 12 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.71-7.66 (m, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.05 (dd, J=9.8, 7.8 Hz, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz, 1H), 5.05 (dd, J=12.5, 5.5 Hz, 1H), 4.00-3.94 (m, 1H), 3.92 (s, 3H), 3.75-3.70 (m, 2H), 3.39-3.33 (m, 4H), 2.88-2.80 (m, 1H), 2.76-2.66 (m, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.15-2.08 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.83-1.68 (m, 6H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺: 856.3097, found, 856.3403.

Compound Example 33: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide. (SIAIS151122)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151027) was used to prepare SIAIS151122 (yellow solid, 4.5 mg, 30%). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J=7.5, 3.5 Hz, 1H), 8.10 (s, 1H), 7.69 (ddd, J=14.0, 7.8, 1.4 Hz, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.40-7.36 (m, 1H), 7.05 (dd, J=10.9, 7.7 Hz, 2H), 6.96 (s, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.04 (dd, J=12.5, 5.5 Hz, 1H), 3.97-3.93 (m, 1H), 3.91 (s, 3H), 3.72-3.68 (m, 2H), 3.36 (t, J=6.8 Hz, 2H), 3.30-3.23 (m, 2H), 2.85-2.76 (m, 1H), 2.75-2.65 (m, 2H), 2.24 (t, J=7.2 Hz, 2H), 2.11-2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.79-1.73 (m, 2H), 1.73-1.67 (m, 4H), 1.51-1.43 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₇P⁺ [M+H]⁺: 870.3254, found, 870.3881.

Compound Example 34: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamide. (SIAIS151123)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151086) was used to prepare SIAIS151123 (yellow solid, 12.3 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.75-7.66 (m, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.04 (t, J=7.5 Hz, 2H), 7.00 (s, 1H) 6.82 (d, J=7.7 Hz, 1H), 5.05 (dd, J=12.5, 5.5 Hz, 1H), 4.01-3.93 (m, 1H), 3.92 (s, 3H), 3.72-3.70 (m, 2H), 3.37-3.32 (m, 4H), 2.89-2.79 (m, 1H), 2.76-2.69 (m, 2H), 2.22 (t, J=7.4 Hz, 2H), 2.14-2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84-1.76 (m, 2H), 1.72-1.64 (m, 4H), 1.50-1.40 (m, 4H). HRMS (ESI) calcd for C₄₄H₅₂ClN₉O₇P⁺ [M+H]⁺: 884.3410, found, 884.3420.

Compound Example 35: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamide. (SIAIS219151)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1204057) was used to prepare SIAIS219151 (yellow solid, 7.2 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.19 (s, 2H), 7.72 (dd, J=13.7, 7.6 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J=8.1 Hz, 1H), 5.18 (dd, J=13.3, 5.1 Hz, 1H), 4.44 (d, J=16.8 Hz, 1H), 4.39 (d, J=16.9 Hz, 1H), 4.15 (s, 1H), 3.95 (s, 3H), 3.73-3.68 (m, 2H), 3.63-3.50 (m, 4H), 2.97-2.90 (m, 1H), 2.85-2.77 (m, 1H), 2.55-2.46 (m, 1H), 2.22-2.15 (m, 3H), 2.00 (s, 2H), 1.86 (d, J=13.5 Hz, 6H). HRMS (ESI) calcd for C₃₉H₄₄ClN₉O₇P⁺ [M+H]⁺: 800.2835, found, 800.2831.

Compound Example 36: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide. (SIAIS219128)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1204085) was used to prepare SIAIS219128 (yellow solid, 10 mg, 40%). ¹H NMR (500 MHz, MeOD) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.79-7.71 (m, 2H), 7.67 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.1 Hz, 1H), 7.44 (s, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.21-7.15 (m, 2H), 7.00 (d, J=8.1 Hz, 1H), 5.20 (dd, J=13.3, 5.0 Hz, 1H), 4.44 (d, J=17.0 Hz, 1H), 4.37 (d, J=17.0 Hz, 1H), 3.98 (s, 4H), 3.82-3.62 (m, 4H), 3.41-3.37 (m, 2H), 3.01-2.89 (m, 1H), 2.83 (d, J=16.7 Hz, 1H), 2.58-2.48 (m, 1H), 2.41 (t, J=6.7 Hz, 2H), 2.28-2.13 (m, 2H), 2.07-1.96 (m, 4H), 1.87 (d, J=13.5 Hz, 6H), 1.77 (d, J=14.2 Hz, 1H). HRMS (ESI) calcd for C₄₁H₄₈ClN₉O₆P⁺ [M+H]⁺: 828.3148, found, 828.3141.

Compound Example 37: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide (SIAIS219152)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1210133) was used to prepare SIAIS219152 (yellow solid, 8.0 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.80-7.71 (m, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.55-7.41 (m, 3H), 7.37-7.25 (m, 1H), 7.22-7.17 (m, 1H), 7.14-7.08 (m, 1H), 5.17 (dd, J=13.2, 5.1 Hz, 1H), 4.53-4.38 (m, 2H), 4.08 (s, 1H), 3.99 (s, 3H), 3.73 (s, 4H), 3.35-3.32 (m, 2H), 2.93-2.90 (m, 1H), 2.83-2.81 (m, 1H), 2.59-2.46 (m, 1H), 2.32 (s, 2H), 2.23-2.07 (m, 5H), 1.87 (d, J=13.6 Hz, 6H), 1.81-1.71 (m, 4H). HRMS (ESI) calcd for C₄₂H₅₀ClN₉O₆P⁺ [M+H]⁺: 842.3305, found, 842.3301.

Compound Example 38: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide. (SIAIS219153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1204061) was used to prepare SIAIS219153 (yellow solid, 8.2 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 8.14 (s, 1H), 7.80-7.71 (m, 2H), 7.68 (t, J=7.4 Hz, 1H), 7.54-7.40 (m, 3H), 7.31-7.25 (m, 1H), 7.21-7.17 (m, 1H), 7.15-7.03 (m, 1H), 5.17 (dd, J=13.3, 5.1 Hz, 1H), 4.48-4.38 (m, 2H), 4.06 (s, 1H), 3.99 (s, 3H), 3.72 (s, 4H), 3.33-3.31 (m, 2H), 2.93-2.90 (m, 1H), 2.82-2.81 (m, 1H), 2.58-2.47 (m, 1H), 2.27 (t, J=6.7 Hz, 2H), 2.24-2.16 (m, 2H), 2.05-2.04 (m, 3H), 1.87 (d, J=13.5 Hz, 6H), 1.76-1.68 (m, 4H), 1.52-1.45 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₂ClN₉O₆P⁺ [M+H]⁺: 856.3461, found, 856.3449.

Compound Example 39: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanamide. (SIAIS219154)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1204063) was used to prepare SIAIS219154 (yellow solid, 7.9 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.22 (s, 1H), 8.17 (s, 1H), 7.79-7.70 (m, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.39 (dd, J=16.2, 8.4 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 5.17 (dd, J=13.3, 5.2 Hz, 1H), 4.42 (d, J=17.0 Hz, 1H), 4.37 (d, J=17.0 Hz, 1H), 4.06 (t, J=10.9 Hz, 1H), 3.98 (s, 3H), 3.69-3.62 (m, 4H), 3.30-3.26 (m, 2H), 2.99-2.89 (m, 1H), 2.85-2.76 (m, 1H), 2.58-2.46 (m, 1H), 2.26-2.15 (m, 5H), 2.04-2.00 (m, 2H), 1.87 (d, J=13.5 Hz, 6H), 1.74-1.65 (m, 4H), 1.51-1.46 (m, 2H), 1.44-1.40 (m, 2H). HRMS (ESI) calcd for C₄₄H₅₄ClN₉O₆P⁺ [M+H]⁺: 870.3618, found, 870.3611.

Compound Example 40: Synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151128)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151010) was used to prepare SIAIS151128 (white solid, 14.7 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.92 (s, 1H), 8.30 (dd, J=8.0, 4.1 Hz, 1H), 8.11 (s, 1H), 7.71-7.64 (m, 2H), 7.61-7.57 (m, 1H), 7.43-7.38 (m, 5H), 7.00 (s, 1H), 6.82 (dd, J=8.5, 2.0 Hz, 1H), 4.72 (s, 1H), 4.59-4.56 (m, 1H), 4.53-4.46 (m, 2H), 4.38 (d, J=15.7 Hz, 1H), 4.13-4.02 (m, 5H), 3.91-3.90 (m, 1H), 3.90 (s, 3H), 3.85-3.65 (m, 8H), 3.37-3.34 (m, 1H), 2.46 (s, 3H), 2.28-2.23 (m, 1H), 2.15-2.07 (m, 3H), 1.99-1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₉PS⁺ [M+H]⁺: 1073.4234, found, 1073.4229.

Compound Example 41: Synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151002) was used to prepare SIAIS151124 (white solid, 6.1 mg, 28%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.30 (dd, J=7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73-7.66 (m, 2H), 7.63-7.59 (m, 1H), 7.47-7.45 (m, 2H), 7.43-7.38 (m, 3H), 7.03 (d, J=2.0 Hz, 1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 4.66 (s, 1H), 4.60-4.54 (m, 1H), 4.51-4.47 (m, 2H), 4.39-4.34 (m, 1H), 4.03-3.96 (m, 1H), 3.91-3.87 (m, 1H), 3.92 (s, 3H), 3.80 (dd, J=11.0, 3.8 Hz, 1H), 3.75-3.70 (m, 6H), 3.64-3.60 (m, 4H), 3.40-3.34 (m, 2H), 2.61-2.53 (m, 1H), 2.49-2.44 (m, 3H), 2.47 (s, 3H), 2.25-2.20 (m, 1H), 2.16-2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84-1.78 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₉PS⁺ [M+H]⁺: 1101.4547, found, 1101.4558.

Compound Example 42: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151125)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151003) was used to prepare SIAIS151125 (white solid, 13.2 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.29 (dd, J=7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73-7.67 (m, 2H), 7.62-7.58 (m, 1H), 7.47-7.44 (m, 2H), 7.43-7.37 (m, 3H), 7.04 (s, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.65 (s, 1H), 4.59-4.50 (m, 2H), 4.50-4.47 (m, 1H), 4.38-4.33 (m, 1H), 4.03-3.97 (m, 1H), 3.92 (s, 3H), 3.89-3.86 (m, 1H), 3.80 (dd, J=10.9, 3.9 Hz, 1H), 3.76-3.70 (m, 6H), 3.64-3.58 (m, 9H), 3.44-3.35 (m, 2H), 2.60-2.54 (m, 1H), 2.50-2.44 (m, 3H), 2.47 (s, 3H), 2.24-2.20 (m, 1H), 2.17-2.13 (m, 2H), 2.10-2.05 (m, 1H), 1.88 (s, 3H), 1.86-1.80 (m, 2H), 1.85 (s, 3H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₅ClN₁₀O₁₀PS⁺ [M+H]⁺: 1145.4809, found, 1145.4807.

Compound Example 43: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide. (SIAIS151126)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151008) was used to prepare SIAIS151126 (white solid, 13.0 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.99 (s, 1H), 8.25 (dd, J=8.1, 4.0 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.70 (dd, J=13.9, 7.7 Hz, 1H), 7.63-7.59 (m, 1H), 7.48-7.46 (m, 2H), 7.44-7.41 (m, 3H), 7.15 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.8, 2.5 Hz, 1H), 4.64 (s, 1H), 4.59-4.51 (m, 2H), 4.50-4.47 (m, 1H), 4.36 (d, J=15.5 Hz, 1H), 4.08-4.01 (m, 1H), 3.93 (s, 3H), 3.90-3.87 (m, 1H), 3.79 (dd, J=10.9, 3.7 Hz, 1H), 3.76-3.71 (m, 6H), 3.62-3.60 (m, 12H), 3.50 (t, J=11.1 Hz, 2H), 2.58-2.53 (m, 1H), 2.49-2.45 (m, 3H), 2.48 (s, 3H), 2.24-2.16 (m, 3H), 2.11-2.05 (m, 1H), 1.94-1.90 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₉ClN₁₀O₁₁PS⁺ [M+H]⁺: 1189.5071, found, 1189.5091.

Compound Example 44: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide. (SIAIS151127)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151009) was used to prepare SIAIS151127 (white solid, 19.5 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 9.05 (s, 1H), 8.23 (dd, J=8.0, 4.1 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.71 (ddd, J=13.9, 7.8, 1.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.50-7.46 (m, 2H), 7.44-7.40 (m, 3H), 7.19 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.8, 2.5 Hz, 1H), 4.64 (s, 1H), 4.58-4.51 (m, 2H), 4.51-4.48 (m, 1H), 4.36 (d, J=15.6 Hz, 1H), 4.09-4.03 (m, 1H), 3.94 (s, 3H), 3.90-3.87 (m, 1H), 3.80 (dd, J=11.0, 3.9 Hz, 1H), 3.76-3.69 (m, 6H), 3.62-3.60 (m, 16H), 3.54 (t, J=12.0 Hz, 2H), 2.59-2.54 (m, 1H), 2.50-2.45 (m, 3H), 2.49 (s, 3H), 2.24-2.18 (m, 3H), 2.11-2.05 (m, 1H), 1.98-1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₃ClN₁₀O₁₂PS⁺ [M+H]⁺: 1233.5333, found, 1233.5335.

Compound Example 45: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) succinamide. (SIAIS164143)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074011) was used to prepare SIAIS164143 (white solid, 12.8 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 9.95 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78-7.73 (m, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.60-7.50 (m, 6H), 7.29 (d, J=8.2 Hz, 1H), 4.62-4.47 (m, 4H), 4.41 (d, J=15.6 Hz, 1H), 4.19-4.11 (m, 1H), 4.00 (s, 3H), 3.91-3.89 (m, 1H), 3.81-3.78 (m, 5H), 2.67-2.53 (m, 4H), 2.59 (s, 3H), 2.31-2.15 (m, 5H), 2.11-2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₇PS⁺ [M+H]⁺: 1013.4023, found, 1013.3452.

Compound Example 46: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide. (SIAIS164144)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074012) was used to prepare SIAIS164144 (white solid, 12.2 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 9.96 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78-7.73 (m, 2H), 7.68 (t, J=7.8 Hz, 1H), 7.61-7.56 (m, 3H), 7.55-7.49 (m, 3H), 7.30 (d, J=8.7 Hz, 1H), 4.64 (s, 1H), 4.69-4.51 (m, 3H), 4.45-4.40 (m, 1H), 4.20-4.12 (m, 1H), 4.00 (s, 3H), 3.93 (d, J=11.2 Hz, 1H), 3.86-3.73 (m, 5H), 2.60 (s, 3H), 2.38-2.17 (m, 9H), 2.11-2.05 (m, 1H), 1.96-1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₇PS⁺ [M+H]⁺: 1027.4179, found, 1027.3585.

Compound Example 47: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide. (SIAIS164145)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074013) was used to prepare SIAIS164145 (white solid, 13.1 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 10.01 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78-7.74 (m, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.59-7.57 (m, 2H), 7.55-7.50 (m, 3H), 7.32 (d, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.61-4.47 (m, 3H), 4.43-4.39 (m, 1H), 4.21-4.13 (m, 1H), 4.00 (s, 3H), 3.92 (d, J=11.1 Hz, 1H), 3.85-3.71 (m, 5H), 2.61 (s, 3H), 2.36-2.17 (m, 9H), 2.10-2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.70-1.62 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₇PS⁺ [M+H]⁺: 1041.4336, found, 1041.3764.

Compound Example 48: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide. (SIAIS164146)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074014) was used to prepare SIAIS164146 (white solid, 12.3 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 9.97 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77-7.73 (m, 2H), 7.68 (t, J=7.8 Hz, 1H), 7.61-7.50 (m, 6H), 7.29 (d, J=8.7 Hz, 1H), 4.64 (s, 1H), 4.61-4.48 (m, 3H), 4.44-4.38 (m, 1H), 4.18-4.12 (m, 1H), 4.00 (s, 3H), 3.91 (d, J=11.1 Hz, 1H), 3.85-3.70 (m, 5H), 2.60 (s, 3H), 2.36-2.15 (m, 9H), 2.10-2.05 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.69-1.61 (m, 4H), 1.42-1.33 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₇PS⁺ [M+H]⁺: 1055.4492, found, 1055.3854.

Compound Example 49: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide. (SIAIS164147)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074015) was used to prepare SIAIS164147 (white solid, 14.8 mg, 69%). ¹H NMR (500 MHz, MeOD) δ 9.91 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77-7.73 (m, 2H), 7.69 (t, J=7.8 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.58-7.51 (m, 5H), 7.31 (d, J=8.7 Hz, 1H), 4.64 (s, 1H), 4.60-4.49 (m, 3H), 4.43-4.38 (m, 1H), 4.20-4.13 (m, 1H), 4.00 (s, 3H), 3.92 (d, J=11.1 Hz, 1H), 3.86-3.75 (m, 5H), 2.60 (s, 3H), 2.33-2.18 (m, 9H), 2.11-2.05 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.68-1.59 (m, 4H), 1.41-1.34 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₇PS⁺ [M+H]⁺: 1069.4649, found, 1069.4001.

Compound Example 50: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N9-((S)-1-((2,4R)-4-hydroxy-2-2S,4R)-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide. (SIAIS164148)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074016) was used to prepare SIAIS164148 (white solid, 12.8 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 10.01 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78-7.73 (m, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.55-7.49 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 4.64 (s, 1H), 4.60-4.49 (m, 3H), 4.44-4.38 (m, 1H), 4.21-4.13 (m, 1H), 4.00 (s, 3H), 3.91 (d, J=11.1 Hz, 1H), 3.85-2.73 (m, 5H), 2.61 (s, 3H), 2.33-2.18 (m, 9H), 2.10-2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.66-1.59 (m, 4H), 1.36 (s, 6H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₇PS⁺ [M+H]⁺: 1083.4805, found, 1083.4133.

Compound Example 51: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide. (SIAIS164149)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074019) was used to prepare SIAIS164149 (white solid, 10.2 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 10.02 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.79-7.73 (m, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.54-7.50 (m, 3H), 7.32 (d, J=8.6 Hz, 1H), 4.64 (s, 1H), 4.60-4.49 (m, 3H), 4.44-4.38 (m, 1H), 4.20-4.14 (m, 1H), 4.00 (s, 3H), 3.91 (d, J=11.2 Hz, 1H), 3.81 (dd, J=10.9, 3.9 Hz, 5H), 2.61 (s, 3H), 2.33-2.18 (m, 9H), 2.10-2.05 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.67-1.57 (m, 4H), 1.35 (s, 9H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₅ClN₁₀O₇PS⁺ [M+H]⁺: 1097.4962, found, 1097.4296.

Compound Example 52: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide. (SIAIS1210117)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074020) was used to prepare SIAIS1210117 (white solid, 10.6 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.72 (dd, J=14.0, 6.7 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.3 Hz, 3H), 7.11 (s, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.66 (s, 1H), 4.62-4.55 (m, 2H), 4.58-4.50 (m, 2H), 4.41-4.36 (m, 1H), 3.95 (s, 3H), 3.92 (d, J=11.1 Hz, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.75 (d, J=12.6 Hz, 2H), 3.47-3.40 (m, 2H), 2.49 (s, 3H), 2.26-2.21 (m, 4H), 2.17 (d, J=12.5 Hz, 2H), 1.90-1.85 (m, 8H), 1.68-1.57 (m, 6H), 1.39-1.33 (m, 10H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₇PS⁺ [M+H]⁺: 1111.5118, found, 1111.5109.

Comparative Example 53: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide. (SIAIS219050)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS219048) was used to prepare SIAIS219050 (white solid, 8.2 mg, 37%). ¹H NMR (500 MHz, MeOD) δ 9.34 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.82-7.71 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.50-7.45 (m, 6H), 7.18 (d, J=8.6 Hz, 1H), 4.56-4.50 (m, 3H), 4.45-4.36 (m, 2H), 4.14-4.10 (m, 1H), 4.04 (dd, J=10.5, 5.1 Hz, 1H), 3.98 (s, 3H), 3.75-3.68 (m, 6H), 2.53 (s, 3H), 2.50-2.40 (m, 1H), 2.34-2.20 (m, 8H), 2.13-2.08 (m, 2H), 2.01-1.94 (m, 1H), 1.87 (d, J=13.5 Hz, 6H), 1.62 (d, J=7.3 Hz, 5H), 1.33 (s, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₇PS⁺ [M+H]⁺: 1111.5118, found, 1111.5111.

Compound Example 54: Synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)succinamide. (SIAIS164157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS164119) was used to prepare SIAIS164157 (yellow solid, 11.0 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 8.16 (s, 1H), 7.80-7.70 (m, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.55 (dd, J=8.4, 7.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.14-7.10 (m, 2H), 7.04 (d, J=7.1 Hz, 1H), 5.08-5.03 (m, 1H), 4.08-4.04 (m, 1H), 3.98 (s, 3H), 3.77-3.61 (m, 4H), 3.49-3.41 (m, 4H), 2.89-2.82 (m, 1H), 2.78-2.68 (m, 2H), 2.53-2.49 (m, 1H), 2.51 (s, 3H), 2.23-2.17 (m, 2H), 2.12-2.00 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H). HRMS (ESI) calcd for C₄₃H₄₉ClN₁₀O₈P⁺ [M+H]⁺: 899.3155, found, 899.0580.

Compound Example 55: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propenamide. (SIAIS219170)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS172147) was used to prepare SIAIS219170 (white solid, 6.4 mg, 39%). ¹H NMR (500 MHz, MeOD) δ 8.24-8.12 (m, 2H), 7.83 (d, J=7.7 Hz, 1H), 7.78-7.71 (m, 4H), 7.65 (s, 1H), 7.47 (d, J=6.7 Hz, 1H), 7.37-7.28 (m, 1H), 7.10-7.04 (m, 1H), 5.12 (dd, J=12.5, 5.4 Hz, 1H), 4.04 (s, 1H), 3.97 (d, J=4.3 Hz, 3H), 3.68-3.61 (m, 4H), 3.16 (t, J=7.2 Hz, 2H), 2.91-2.82 (m, 1H), 2.78-2.66 (m, 2H), 2.63 (s, 2H), 2.16-2.06 (m, 3H), 1.87 (d, J=13.5 Hz, 6H), 1.89-1.85 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₃ClN₈O₇P⁺ [M+H]⁺: 813.2675, found, 813.2670.

Compound Example 56: Synthesis of 4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164007)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151001) was used to prepare SIAIS164007 (yellow solid, 17.5 mg, 71%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.72-7.65 (m, 1H), 7.61-7.54 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.52 (d, J=8.5 Hz, 1H), 5.10 (dd, J=12.7, 5.5 Hz, 1H), 3.86 (s, 3H), 3.84-3.75 (m, 6H), 3.53-3.51 (m, 4H), 3.43-3.32 (m, 2H), 3.30-2.95 (m, 5H), 2.90-2.83 (m, 2H), 2.81-2.54 (m, 5H), 2.21-2.01 (m, 3H), 1.89 (d, J=13.6 Hz, 6H), 1.83-1.63 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₅ClN₁₀O₈P [M+H]⁺: 941.3625, found, 941.2930.

Compound Example 57: Synthesis of 4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy) ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164008)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151004) was used to prepare SIAIS164008 (yellow solid, 18.4 mg, 71%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J=14.7, 7.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.37 (t, J=7.0 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.52 (d, J=8.2 Hz, 1H), 5.07 (dd, J=12.5, 5.5 Hz, 1H), 3.89 (s, 1H), 3.87 (s, 1H), 3.84 (s, 3H), 3.78 (t, J=5.8 Hz, 2H), 3.73 (t, J=5.1 Hz, 2H), 3.69-3.68 (m, 2H), 3.67-3.63 (m, 2H), 3.51 (t, J=5.1 Hz, 3H), 3.38-3.31 (m, 8H), 2.91-2.63 (m, 7H), 2.18 (d, J=10.2 Hz, 2H), 2.15-2.05 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.86-1.73 (m, 2H). HRMS (ESI) calcd for C₄₈H₅₉ClN₁₀O₉P [M+H]⁺: 985.3887, found, 985.3166.

Compound Example 58: Synthesis of 4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164009)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151005) was used to prepare SIAIS164009 (yellow solid, 20 mg, 74%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (d, J=14.7 Hz, 1H), 7.67 (dd, J=14.7, 7.1 Hz, 1H), 7.61-7.51 (m, 2H), 7.37 (t, J=7.1 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.08 (t, J=6.2 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.53 (d, J=9.0 Hz, 1H), 5.05 (dd, J=12.5, 5.5 Hz, 1H), 3.91 (d, J=12.4 Hz, 2H), 3.84 (s, 3H), 3.80-3.70 (m, 5H), 3.70-3.63 (m, 7H), 3.63-3.57 (m, 3H), 3.51-3.49 (m, 3H), 3.46-3.35 (m, 2H), 3.32-3.31 (m, 3H), 2.92-2.77 (m, 4H), 2.77-2.62 (m, 3H), 2.22 (d, J=12.1 Hz, 2H), 2.12-2.08 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.86-1.79 (m, 2H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₁₀P [M+H]⁺: 1029.4149, found, 1029.3401.

Compound Example 59: Synthesis of 4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164016)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151006) was used to prepare SIAIS164016 (yellow solid, 13 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J=13.3, 8.4 Hz, 1H), 7.60-7.51 (m, 2H), 7.37 (t, J=7.1 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.55 (d, J=7.7 Hz, 1H), 5.04 (dd, J=12.7, 5.5 Hz, 1H), 3.93 (d, J=12.7 Hz, 2H), 3.84 (s, 3H), 3.75 (t, J=5.8 Hz, 3H), 3.71 (t, J=5.2 Hz, 2H), 3.69-3.55 (m, 15H), 3.54-3.36 (m, 5H), 2.86-2.80 (m, 4H), 2.77-2.63 (m, 3H), 2.25 (d, J=11.3 Hz, 2H), 2.15-2.04 (m, 1H), 1.90-1.86 (m, 8H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₁₁P [M+H]⁺: 1073.4411, found, 1073.4778.

Compound Example 60: Synthesis of 4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164017)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151007) was used to prepare SIAIS164017 (yellow solid, 18.2 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.05 (s, 1H), 7.67 (dd, J=14.2, 6.5 Hz, 1H), 7.60-7.52 (m, 2H), 7.37 (t, J=6.9 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.04 (dd, J=12.6, 5.5 Hz, 1H), 3.95 (d, J=12.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J=12.5, 6.6 Hz, 2H), 3.71 (t, J=5.2 Hz, 2H), 3.68-3.56 (m, 18H), 3.56-3.37 (m, 5H), 3.32-3.31 (m, 4H), 2.93-2.78 (m, 4H), 2.78-2.60 (m, 3H), 2.25 (d, J=10.6 Hz, 2H), 2.11-2.07 (m, 1H), 1.90-1.87 (m, 8H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₁₂P [M+H]⁺: 1117.4674, found, 1117.4682.

Compound Example 61: Synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164018)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151025) was used to prepare SIAIS164018 (yellow solid, 18.1 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.07 (d, J=17.8 Hz, 1H), 7.68 (dd, J=14.1, 7.7 Hz, 1H), 7.61-7.53 (m, 2H), 7.37 (t, J=7.5 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.60 (d, J=7.9 Hz, 1H), 5.09 (dd, J=12.5, 5.5 Hz, 1H), 4.26 (s, 2H), 3.97 (d, J=12.4 Hz, 2H), 3.86 (s, 3H), 3.71-3.32 (m, 9H), 2.98-2.81 (m, 3H), 2.79-2.68 (m, 2H), 2.27 (d, J=11.4 Hz, 2H), 2.17-2.08 (m, 1H), 2.00-1.91 (m, 2H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₄₉ClN₁₀O₇P [M+H]⁺: 883.3206, found, 883.3327.

Compound Example 62: Synthesis of 4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164019)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151026) was used to prepare SIAIS164019 (yellow solid, 14.2 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J=13.4, 8.4 Hz, 1H), 7.63-7.53 (m, 2H), 7.38 (t, J=6.8 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 5.05 (dd, J=12.5, 5.4 Hz, 1H), 3.93 (s, 2H), 3.86 (s, 3H), 3.72 (t, J=5.2 Hz, 2H), 3.40 (t, J=12.2 Hz, 2H), 3.32-3.31 (m, 6H), 2.86-2.79 (m, 5H), 2.77-2.64 (m, 3H), 2.17 (d, J=12.1 Hz, 2H), 2.14-2.06 (m, 1H), 1.90-1.83 (m, 8H). HRMS (ESI) calcd for C₄₄H₅₁ClN₁₀O₇P [M+H]⁺: 897.3363, found, 897.3679.

Compound Example 63: Synthesis of 4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164020)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151019) was used to prepare SIAIS164020 (yellow solid, 14.2 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=13.4, 8.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.39 (t, J=7.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.08 (d, J=6.9 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 5.07 (dd, J=12.6, 5.5 Hz, 1H), 3.94 (d, J=12.4 Hz, 2H), 3.86 (s, 3H), 3.59-3.37 (m, 5H), 3.33-3.31 (m, 6H), 2.89-2.80 (m, 3H), 2.79-2.68 (m, 2H), 2.58 (s, 2H), 2.19 (s, 2H), 2.13-2.11 (m, 1H), 2.08-1.97 (m, 2H), 1.97-1.80 (m, 8H). HRMS (ESI) calcd for C₄₅H₅₃ClN₁₀O₇P [M+H]⁺: 911.3519, found, 911.3859.

Compound Example 64: Synthesis of 4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164021)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151020) was used to prepare SIAIS164021 (yellow solid, 20.6 mg, 85%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.69 (dd, J=13.9, 7.5 Hz, 1H), 7.61-7.56 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 5.07 (dd, J=12.7, 5.5 Hz, 1H), 3.95 (s, 2H), 3.86 (s, 3H), 3.66 (m, 3H), 3.52-3.37 (m, 5H), 2.97-2.80 (m, 4H), 2.80-2.66 (m, 2H), 2.54 (s, 2H), 2.36 (t, J=8.1 Hz, 1H), 2.27 (s, 2H), 2.17-2.08 (m, 1H), 2.04 (dt, J=14.8, 7.5 Hz, 1H), 1.94 (s, 2H), 1.89 (d, J=13.6 Hz, 6H), 1.75 (s, 4H). HRMS (ESI) calcd for C₄₆H₅₅ClN₁₀O₇P [M+H]⁺: 925.3676, found, 925.4004.

Compound Example 65: Synthesis of 4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164022)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151027) was used to prepare SIAIS164022 (yellow solid, 15.5 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (d, J=17.1 Hz, 1H), 7.68 (dd, J=13.4, 7.1 Hz, 1H), 7.60-7.55 (m, 2H), 7.38 (t, J=7.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.06 (dd, J=9.2, 7.9 Hz, 2H), 6.74 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 5.06 (dd, J=12.5, 5.5 Hz, 1H), 3.95 (d, J=11.7 Hz, 2H), 3.86 (s, 3H), 3.77-3.39 (m, 4H), 3.37 (t, J=6.8 Hz, 2H), 3.35-3.31 (m, 5H), 2.91-2.80 (m, 3H), 2.80-2.64 (m, 2H), 2.49 (t, J=7.3 Hz, 2H), 2.24 (d, J=12.1 Hz, 2H), 2.19-2.04 (m, 1H), 1.90-1.87 (m, 8H), 1.78-1.65 (m, 4H), 1.57-1.43 (m, 2H). HRMS (ESI) calcd for C₄₇H₅₇ClN₁₀O₇P [M+H]⁺: 939.3832, found, 939.4168.

Compound Example 66: Synthesis of 4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164023)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151086) was used to prepare SIAIS164023 (yellow solid, 14.1 mg, 56%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=12.8, 7.8 Hz, 1H), 7.56 (dd, J=8.6, 7.1 Hz, 2H), 7.38 (t, J=7.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.8 Hz, 2H), 6.74 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 5.06 (dd, J=12.5, 5.5 Hz, 1H), 3.96 (d, J=12.7 Hz, 2H), 3.87 (s, 3H), 3.71-3.46 (m, 4H), 3.40-3.31 (m, 7H), 2.93-2.80 (m, 3H), 2.80-2.65 (m, 2H), 2.45 (t, J=7.5 Hz, 2H), 2.25 (d, J=11.5 Hz, 2H), 2.15-2.06 (m, 1H), 1.90-1.87 (m, 8H), 1.71-1.62 (m, 4H), 1.58-1.39 (m, 4H). HRMS (ESI) calcd for C₄₈H₅₉ClN₁₀O₇P [M+H]⁺: 953.3989, found, 953.4144.

Compound Example 67: Synthesis of 3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219073)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1204057) was used to prepare SIAIS219073 (yellow solid, 5.8 mg, 38%). ¹H NMR (500 MHz, MeOD) δ 8.33 (s, 1H), 8.11 (s, 1H), 7.74-7.68 (m, 1H), 7.60 (s, 1H), 7.45-7.36 (m, 3H), 7.18 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.80 (d, J=7.0 Hz, 1H), 5.19-5.15 (m, 1H), 4.44 (d, J=16.8 Hz, 1H), 4.37 (d, J=16.8 Hz, 1H), 4.25 (s, 1H), 3.96 (d, J=12.7 Hz, 2H), 3.90 (s, 3H), 3.64-3.61 (m, 4H), 3.39-3.36 (m, 2H), 3.28-3.05 (m, 6H), 2.97-2.87 (m, 1H), 2.81 (d, J=2.5 Hz, 1H), 2.54-2.50 (m, 1H), 2.37 (d, J=11.1 Hz, 2H), 2.24-2.07 (m, 3H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₅₁ClN₁₀O₆P⁺ [M+H]⁺: 869.3414, found, 869.3410.

Compound Example 68: Synthesis of 3-(4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219155)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1204085) was used to prepare SIAIS219155 (yellow solid, 7.0 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.33 (s, 1H), 8.09 (s, 1H), 7.70 (dd, J=14.0, 7.8 Hz, 1H), 7.60 (s, 1H), 7.43 (t, J=7.6 Hz, 2H), 7.38 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 5.17 (dd, J=13.2, 5.0 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 4.34 (d, J=17.4 Hz, 1H), 3.97-3.87 (m, 4H), 3.77-3.47 (m, 2H), 3.46-3.31 (m, 8H), 3.17-3.05 (m, 4H), 2.97-2.89 (m, 1H), 2.85-2.78 (m, 1H), 2.58-2.49 (m, 3H), 2.32-2.17 (m, 3H), 2.09-1.92 (m, 4H), 1.88 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₅ClN₁₀O₆P⁺[M+H]⁺: 897.3727, found, 897.3722.

Compound Example 69: Synthesis of 3-(4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219156)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1210133) was used to prepare SIAIS219156 (yellow solid, 7.5 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 8.30 (s, 1H), 8.12 (s, 1H), 7.71 (dd, J=13.4, 7.1 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H), 7.47 (dt, J=12.9, 7.1 Hz, 3H), 7.37 (d, J=7.4 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 5.18 (dd, J=13.3, 5.2 Hz, 1H), 4.50 (d, J=17.1 Hz, 1H), 4.43 (d, J=17.1 Hz, 1H), 3.95 (s, 1H), 3.91 (s, 3H), 3.77-3.47 (m, 4H), 3.38 (d, J=3.4 Hz, 2H), 3.30-3.22 (m, 8H), 2.97-2.88 (m, 1H), 2.84-2.78 (m, 1H), 2.56-2.49 (m, 3H), 2.36 (s, 2H), 2.26-2.18 (m, 1H), 2.12-2.10 (m, 2H), 1.88 (d, J=13.6 Hz, 6H), 1.77 (s, 4H). HRMS (ESI) calcd for C₄₆H₅₇ClN₁₀O₆P⁺ [M+H]⁺: 911.3883, found, 911.3878.

Compound Example 70: Synthesis of 3-(4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1204061) was used to prepare SIAIS219157 (yellow solid, 8.1 mg, 53%). ¹H NMR (500 MHz, MeOD) δ 8.28 (s, 1H), 8.13 (s, 1H), 7.71 (dd, J=14.0, 7.7 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.45 (t, J=6.5 Hz, 3H), 7.25 (d, J=7.9 Hz, 1H), 7.08 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 5.19 (dd, J=13.3, 5.1 Hz, 1H), 4.54 (d, J=17.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 3.95 (s, 1H), 3.91 (s, 3H), 3.67-3.57 (m, 4H), 3.38 (t, J=7.1 Hz, 2H), 3.30-3.17 (m, 8H), 2.99-2.88 (m, 1H), 2.85-2.77 (m, 1H), 2.59-2.44 (m, 3H), 2.39 (d, J=10.6 Hz, 2H), 2.27-2.08 (m, 3H), 1.88 (d, J=13.6 Hz, 6H), 1.78-1.74 (m, 2H), 1.73-1.65 (m, 2H), 1.56-1.47 (m, 2H). HRMS (ESI) calcd for C₄₇H₅₉ClN₁₀O₆P [M+H]⁺: 925.4040, found, 925.4031.

Compound Example 71: Synthesis of 3-(4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1204063) was used to prepare SIAIS219124 (yellow solid, 11.2 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.70 (dd, J=13.9, 7.9 Hz, 1H), 7.59 (s, 1H), 7.45-7.37 (m, 2H), 7.33 (s, 1H), 7.16 (d, J=7.3 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.64 (d, J=8.4 Hz, 1H), 5.17 (dd, J=13.2, 5.0 Hz, 1H), 4.38 (d, J=17.0 Hz, 1H), 4.31 (d, J=16.9 Hz, 1H), 3.98 (d, J=12.6 Hz, 2H), 3.89 (d, J=14.3 Hz, 3H), 3.57 (s, 2H), 3.47 (s, 2H), 3.19 (s, 6H), 2.95-2.89 (m, 4H), 2.82 (d, J=15.7 Hz, 2H), 2.54-2.41 (m, 3H), 2.34-2.18 (m, 4H), 1.97-1.86 (m, 6H), 1.71-1.64 (m, 4H), 1.48 (s, 4H). HRMS (ESI) calcd for C₄₈H₆₁ClN₁₀O₆P [M+H]⁺: 939.4196, found, 939.4188.

Compound Example 72: Synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164041)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151010) was used to prepare SIAIS164041 (white solid, 18.2 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=14.1, 7.7 Hz, 1H), 7.60-7.55 (m, 1H), 7.46-7.37 (m, 5H), 7.30 (s, 1H), 6.72 (d, J=2.5 Hz, 1H), 6.58 (d, J=8.7 Hz, 1H), 4.72 (s, 1H), 4.60-4.49 (m, 3H), 4.48-4.23 (m, 5H), 4.14-4.00 (m, 3H), 3.95 (d, J=12.2 Hz, 2H), 3.91-3.83 (m, 5H), 3.82-3.74 (m, 7H), 3.48-3.44 (m, 2H), 2.85 (t, J=12.2 Hz, 2H), 2.46 (s, 3H), 2.29-2.23 (m, 3H), 2.14-2.05 (m, 1H), 1.90-1.87 (m, 9H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₄ClN₁₁O₉PS⁺ [M+H]⁺: 1142.4812, found, 1142.4776.

Compound Example 73: Synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164032)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151002) was used to prepare SIAIS164032 (white solid, 15.4 mg, 50%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=14.0, 7.6 Hz, 1H), 7.62-7.51 (m, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.45-7.36 (m, 3H), 7.29 (d, J=9.4 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 6.60 (d, J=7.4 Hz, 1H), 4.66 (s, 1H), 4.60-4.50 (m, 3H), 4.37 (d, J=15.5 Hz, 1H), 3.97 (d, J=13.1 Hz, 2H), 3.89 (d, J=11.2 Hz, 1H), 3.85 (s, 3H), 3.84-3.80 (m, 1H), 3.80-3.67 (m, 5H), 3.66-3.51 (m, 6H), 3.51-3.36 (m, 2H), 3.30 (s, 5H), 2.91-2.85 (m, 2H), 2.78-2.61 (m, 2H), 2.61-2.42 (m, 5H), 2.28-2.21 (m, 3H), 2.11-2.04 (m, 1H), 1.93-1.87 (m, 7H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₈ClN₁₁O₉PS⁺ [M+H]⁺: 1170.5125, found, 1170.5152.

Compound Example 74: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164033)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151003) was used to prepare SIAIS164033 (white solid, 24.9 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.98 (s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=14.0, 7.6 Hz, 1H), 7.62-7.52 (m, 1H), 7.51-7.46 (m, 2H), 7.45-7.42 (m, 2H), 7.39 (t, J=7.2 Hz, 1H), 7.28 (s, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.65 (s, 1H), 4.60-4.47 (m, 3H), 4.37 (d, J=15.6 Hz, 1H), 3.98 (d, J=12.7 Hz, 2H), 3.89 (d, J=11.2 Hz, 1H), 3.85 (s, 3H), 3.83-3.69 (m, 6H), 3.66-3.57 (m, 9H), 3.52-3.41 (m, 2H), 3.32-3.31 (m, 5H), 2.92-2.86 (m, 2H), 2.65-2.63 (m, 2H), 2.62-2.53 (m, 1H), 2.53-2.43 (m, 4H), 2.33-2.18 (m, 3H), 2.10-2.05 (m, 1H), 1.94-1.87 (m, 8H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₂ClN₁₁O₁₀PS⁺ [M+H]⁺: 1214.5387, found, 1214.5405.

Compound Example 75: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164034)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151008) was used to prepare SIAIS164034 (white solid, 23.8 mg, 72%). ¹H NMR (500 MHz, MeOD) δ 8.94 (d, J=3.1 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J=13.5, 8.4 Hz, 1H), 7.62-7.52 (m, 1H), 7.51-7.45 (m, 2H), 7.45-7.41 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 7.29 (s, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 4.65 (s, 1H), 4.59-4.50 (m, 3H), 4.36 (d, J=15.5 Hz, 1H), 3.98 (d, J=12.7 Hz, 2H), 3.92-3.83 (m, 4H), 3.82-3.70 (m, 6H), 3.65-3.56 (m, 14H), 3.47-3.44 (m, 2H), 3.32 (s, 6H), 2.87 (t, J=12.5 Hz, 2H), 2.67-2.54 (m, 2H), 2.51-2.43 (m, 4H), 2.32-2.18 (m, 3H), 2.10-2.04 (m, 1H), 1.93-1.87 (m, 7H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₆ClN₁₁O₁₁PS⁺ [M+H]⁺: 1258.5650, found, 1258.5713.

Compound Example 76: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164035)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151009) was used to prepare SIAIS164035 (white solid, 18.7 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.52-8.25 (m, 1H), 8.05 (s, 1H), 7.68 (dd, J=14.8, 7.1 Hz, 1H), 7.60-7.55 (m, 1H), 7.51-7.46 (m, 2H), 7.45-7.41 (m, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.28 (s, 1H), 6.74 (s, 1H), 6.61 (s, 1H), 4.65 (s, 1H), 4.59-4.49 (m, 3H), 4.36 (d, J=15.5 Hz, 1H), 3.98 (d, J=13.0 Hz, 2H), 3.92-3.83 (m, 4H), 3.82-3.67 (m, 7H), 3.62-3.61 (m, 20H), 3.49-3.44 (m, 2H), 3.34-3.31 (m, 2H), 2.87 (t, J=12.5 Hz, 2H), 2.68-2.53 (m, 2H), 2.51-2.44 (m, 4H), 2.28-2.20 (m, 3H), 2.10-2.04 (m, 1H), 1.94-1.87 (m, 8H), 1.04 (s, 9H). HRMS (ESI) calcd for C₆₄H₉₀ClN₁₁O₁₂PS⁺ [M+H]⁺: 1302.5912, found, 1302.5944.

Compound Example 77: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164120)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074011) was used to prepare SIAIS164120 (white solid, 9.1 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 9.62 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.70 (dd, J=14.0, 9.1 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.43 (t, J=7.7 Hz, 2H), 6.98 (s, 1H), 6.80 (s, 1H), 4.61 (s, 1H), 4.59-4.54 (m, 2H), 4.50 (s, 1H), 4.40 (d, J=15.8 Hz, 1H), 4.34-4.22 (m, 1H), 3.97 (d, J=11.9 Hz, 2H), 3.92-3.86 (m, 4H), 3.81 (dd, J=11.0, 3.9 Hz, 1H), 3.67-3.60 (m, 5H), 3.17 (s, 4H), 2.84-2.57 (m, 5H), 2.56 (s, 3H), 2.37 (d, J=10.3 Hz, 2H), 2.28-2.19 (m, 1H), 2.19-2.05 (m, 3H), 1.88 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₀ClN₁₁O₇PS⁺ [M+H]⁺: 1082.4601, found, 1082.1363.

Compound Example 78: Synthesis of (2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164121)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074012) was used to prepare SIAIS164121 (white solid, 6.3 mg, 33%). ¹H NMR (500 MHz, MeOD) δ 9.72 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J=13.9, 7.9 Hz, 1H), 7.67-7.60 (m, 1H), 7.59-7.35 (m, 6H), 7.14 (s, 1H), 6.91 (s, 1H), 4.69-4.49 (m, 5H), 4.41 (d, J=15.8 Hz, 1H), 4.31-4.16 (m, 1H), 3.95-3.92 (m, 6H), 3.81 (d, J=7.8 Hz, 1H), 3.69 (s, 4H), 3.27-3.02 (m, 5H), 2.57 (s, 3H), 2.44-2.37 (m, 6H), 2.24-2.08 (m, 4H), 1.93-1.87 (m, 8H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₂ClN₁₁O₇PS⁺ [M+H]⁺: 1096.4758, found, 1096.1472.

Compound Example 79: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164122)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074013) was used to prepare SIAIS164122 (white solid, 8.6 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.76 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J=13.9, 7.8 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.59-7.43 (m, 6H), 7.17 (s, 1H), 6.95 (s, 1H), 4.64 (s, 1H), 4.61-4.49 (m, 3H), 4.41 (d, J=15.6 Hz, 1H), 4.25 (s, 1H), 3.99-3.88 (m, 6H), 3.81 (dd, J=10.8, 3.8 Hz, 1H), 3.69 (s, 4H), 3.40-3.31 (m, 3H), 3.17 (s, 3H), 2.58 (s, 3H), 2.50-2.43 (m, 4H), 2.36-2.22 (m, 5H), 2.13-2.03 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.67 (s, 4H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₄ClN₁₁O₇PS⁺ [M+H]⁺: 1110.4914, found, 1110.1540.

Compound Example 80: Synthesis of (2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164123)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074014) was used to prepare SIAIS164123 (white solid, 8.4 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.64 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.71 (dd, J=13.9, 7.7 Hz, 1H), 7.61 (s, 1H), 7.55-7.44 (m, 6H), 7.01 (s, 1H), 6.81 (s, 1H), 4.64 (s, 1H), 4.60-4.50 (m, 3H), 4.41 (d, J=15.7 Hz, 1H), 3.96 (d, J=10.3 Hz, 2H), 3.92-3.90 (m, 4H), 3.81 (dd, J=10.9, 3.9 Hz, 1H), 3.69-3.60 (m, 4H), 3.31-3.17 (m, 7H), 2.56 (s, 3H), 2.47 (t, J=7.3 Hz, 2H), 2.37 (s, 2H), 2.35-2.27 (m, 2H), 2.27-2.20 (m, 1H), 2.19-2.03 (m, 3H), 1.88 (d, J=13.6 Hz, 6H), 1.70-1.59 (m, 4H), 1.43-1.37 (m, 2H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₆ClN₁₁O₇PS⁺ [M+H]⁺: 1124.5071, found, 1124.1726.

Compound Example 81: Synthesis of (2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074015) was used to prepare SIAIS164124 (white solid, 8.3 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 9.76 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J=14.0, 7.9 Hz, 1H), 7.63 (s, 1H), 7.59-7.39 (m, 6H), 7.19 (s, 1H), 6.94 (s, 1H), 4.64 (s, 1H), 4.62-4.46 (m, 3H), 4.41 (d, J=15.7 Hz, 1H), 4.26 (s, 1H), 4.03-3.86 (m, 6H), 3.81 (dd, J=10.9, 3.8 Hz, 1H), 3.69 (s, 4H), 3.33 (s, 3H), 3.17 (s, 3H), 2.58 (s, 3H), 2.53-2.38 (m, 4H), 2.38-2.17 (m, 5H), 2.13-2.02 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.64 (d, J=6.7 Hz, 4H), 1.39 (d, J=3.5 Hz, 4H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₈ClN₁₁O₇PS⁺ [M+H]⁺: 1138.5227, found, 1138.1798.

Compound Example 82: Synthesis of (2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164125)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074016) was used to prepare SIAIS164125 (white solid, 8.9 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.82-9.70 (m, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.78-7.68 (m, 1H), 7.64 (s, 1H), 7.56-7.47 (m, 6H), 7.23 (s, 1H), 6.98 (s, 1H), 4.64 (s, 1H), 4.61-4.47 (m, 3H), 4.40 (d, J=15.7 Hz, 1H), 4.25 (s, 1H), 3.92 (t, J=8.1 Hz, 6H), 3.81 (dd, J=11.0, 3.8 Hz, 1H), 3.70 (s, 4H), 3.39-3.32 (m, 3H), 3.30-3.17 (m, 3H), 2.58 (s, 3H), 2.52-2.39 (m, 4H), 2.39-2.17 (m, 5H), 2.13-2.03 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.62 (s, 4H), 1.37 (s, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₉H₈₀ClN₁₁O₇PS⁺ [M+H]⁺: 1152.5384, found, 1152.1936.

Compound Example 83: Synthesis of (2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164126)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074019) was used to prepare SIAIS164126 (white solid, 7.7 mg, 38%). ¹H NMR (500 MHz, MeOD) δ 9.88-9.79 (m, 1H), 8.19 (s, 2H), 7.73 (dd, J=13.9, 7.8 Hz, 1H), 7.65 (s, 1H), 7.57-7.48 (m, 6H), 7.33 (s, 1H), 7.06 (s, 1H), 4.64 (s, 1H), 4.61-4.46 (m, 3H), 4.44-4.37 (m, 1H), 4.27 (s, 1H), 3.95-3.90 (m, 6H), 3.85-3.48 (m, 8H), 3.20-3.04 (m, 3H), 2.60 (s, 3H), 2.53-2.43 (m, 4H), 2.42-2.19 (m, 5H), 2.10-2.05 (m, 1H), 1.88 (d, J=13.6 Hz, 6H), 1.62 (d, J=7.0 Hz, 4H), 1.36 (s, 8H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₂ClN₁₁O₇PS⁺ [M+H]⁺: 1166.5540, found, 1166.2102.

Compound Example 84: Synthesis of 4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide. (SIAIS164152)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS164119) was used to prepare SIAIS164152 (yellow solid, 10.6 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 8.17 (s, 1H), 7.74 (dd, J=13.8, 7.8 Hz, 1H), 7.71-7.62 (m, 2H), 7.57 (dd, J=8.5, 7.2 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.45 (s, 1H), 7.15 (t, J=6.9 Hz, 2H), 7.06 (d, J=7.1 Hz, 1H), 5.08 (dd, J=12.7, 5.5 Hz, 1H), 4.72 (s, 1H), 4.27 (s, 1H), 3.97 (s, 3H), 3.93 (d, J=12.2 Hz, 2H), 3.86-3.58 (m, 6H), 3.48 (s, 5H), 3.17 (s, 2H), 2.93-2.85 (m, 1H), 2.80-2.65 (m, 3H), 2.65-2.40 (m, 7H), 2.16-2.07 (m, 1H), 1.87 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₇H₅₆ClN₁₁O₈P [M+H]⁺: 968.3734, found, 968.1075.

Compound Example 85: Synthesis of 4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS219158)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS172147) was used to prepare SIAIS219158 (white solid, 6.8 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 8.31 (d, J=12.2 Hz, 1H), 8.11 (s, 1H), 7.86-7.81 (m, 2H), 7.76 (dd, J=7.8, 1.2 Hz, 1H), 7.74-7.67 (m, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.1 Hz, 2H), 6.99 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.13 (dd, J=12.6, 5.5 Hz, 1H), 3.94 (d, J=12.8 Hz, 2H), 3.90 (s, 3H), 3.61-3.55 (m, 4H), 3.19-3.14 (m, 8H), 2.91-2.77 (m, 4H), 2.76-2.73 (m, 2H), 2.35 (d, J=11.4 Hz, 2H), 2.18-2.06 (m, 3H), 1.91-1.87 (m, 6H). HRMS (ESI) calcd for C₄₄H₅₀ClN₉O₇P⁺ [M+H]⁺: 882.3254, found, 882.3242.

Compound Example 86: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS164128) was used to prepare SIAIS164153 (white solid, 9.2 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.90 (s, 1H), 8.32 (s, 1H), 8.21 (s, 2H), 7.74 (dd, J=13.7, 7.7 Hz, 1H), 7.69-7.58 (m, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.54-7.46 (m, 3H), 7.38 (s, 1H), 7.10 (s, 1H), 4.64-4.48 (m, 6H), 4.44-4.41 (m, 1H), 4.26 (s, 1H), 3.96-3.92 (m, 6H), 3.88-3.53 (m, 8H), 3.17 (s, 2H), 2.92 (s, 2H), 2.61-2.59 (m, 5H), 2.52 (s, 2H), 2.48-2.13 (m, 8H), 2.12-2.01 (m, 3H), 1.87 (d, J=13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₇₉ClN₁₄O₇PS⁺ [M+H]⁺: 1205.5398, found, 1205.1640.

Compound Example 87: Synthesis of 8-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164011)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151001) was used to prepare SIAIS164011 (yellow solid, 16.6 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.09 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J=8.1, 1.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.61 (t, J=5.7 Hz, 1H), 5.04 (dd, J=12.8, 5.4 Hz, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.63 (t, J=5.2 Hz, 6H), 3.48 (dd, J=10.9, 5.4 Hz, 2H), 2.98-2.90 (m, 4H), 2.89-2.81 (m, 1H), 2.73 (q, J=7.5 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H), 2.56-2.49 (m, 2H), 2.00-1.97 (m, 1H), 1.73 (s, 6H), 1.27 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₇ [M+H]⁺: 770.3297, found, 770.2435.

Compound Example 88: Synthesis of 8-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164012)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151004) was used to prepare SIAIS164012 (yellow solid, 28 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.70 (s, 1H), 8.51-8.43 (m, 2H), 8.27 (s, 1H), 7.77 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.13 (s, 1H), 7.03-7.02 (m, 1H), 6.84 (dd, J=8.6, 5.0 Hz, 1H), 6.43 (s, 1H), 4.96 (dd, J=11.8, 5.4 Hz, 1H), 3.88-3.83 (m, 4H), 3.71-3.65 (m, 8H), 3.37 (s, 2H), 3.03-2.93 (m, 4H), 2.90-2.88 (m, 1H), 2.77-2.71 (m, 6H), 2.13 (s, 1H), 1.70 (dd, J=7.3, 2.1 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₈ [M+H]⁺: 814.3559, found, 814.2643.

Compound Example 89: Synthesis of 8-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164013)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151005) was used to prepare SIAIS164013 (yellow solid, 28.8 mg, 73%). ¹H NMR (500 MHz, CDCl₃) δ 10.76 (s, 1H), 9.09 (s, 1H), 8.47 (d, J=8.2 Hz, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.41 (dd, J=10.1, 5.5 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.42 (s, 1H), 5.03-4.87 (m, 1H), 3.83 (t, J=6.2 Hz, 4H), 3.70-3.57 (m, 12H), 3.35 (s, 2H), 3.02-2.84 (m, 5H), 2.83-2.65 (m, 6H), 2.12 (s, 1H), 1.88-1.65 (m, 6H), 1.37-1.26 (m, 3H). HRMS (ESI) calcd for C₄₇H₅₂N₇O₉ [M+H]⁺: 858.3821, found, 858.2862.

Compound Example 90: Synthesis of 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164014)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151006) was used to prepare SIAIS164014 (yellow solid, 16.8 mg, 40%). ¹H NMR (500 MHz, CDCl₃) δ 10.04 (s, 1H), 8.62 (s, 1H), 8.49 (d, J=8.2 Hz, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.54 (dd, J=8.2, 1.3 Hz, 1H), 7.48-7.41 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.43 (s, 1H), 4.94 (dd, J=12.2, 5.4 Hz, 1H), 3.82 (t, J=6.3 Hz, 4H), 3.73-3.57 (m, 16H), 3.38 (t, J=5.1 Hz, 2H), 3.02-2.94 (m, 4H), 2.91-2.88 (m, 1H), 2.83-2.67 (m, 6H), 2.18-2.08 (m, 1H), 1.73 (d, J=5.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₉H₅₆N₇O₁₀ [M+H]⁺: 902.4083, found, 902.4401.

Compound Example 91: Synthesis of 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164015)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151007) was used to prepare SIAIS164015 (yellow solid, 17.8 mg, 41%). ¹H NMR (500 MHz, CDCl₃) δ 10.12 (s, 1H), 8.64 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.28 (s, 1H), 7.74 (d, J=4.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.45 (dd, J=12.4, 5.4 Hz, 1H), 7.17 (s, 1H), 7.09-7.02 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.46 (s, 1H), 4.94 (dd, J=12.0, 5.6 Hz, 1H), 3.83 (d, J=3.2 Hz, 4H), 3.74-3.60 (m, 20H), 3.41 (d, J=4.8 Hz, 2H), 2.98 (s, 4H), 2.91-2.88 (m, 1H), 2.81-2.69 (m, 6H), 2.15-2.13 (m, 1H), 1.74-1.71 (m, 6H), 1.34 (t, J=7.4 Hz, 3H). HRMS (ESI) calcd for C₅₁H₆₀N₇O₁₁ [M+H]⁺: 946.4345, found, 946.4364.

Compound Example 92: Synthesis of 8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164028)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151025) was used to prepare SIAIS164028 (yellow solid, 17.2 mg, 53%). ¹H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 11.11 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.65-7.60 (m, 2H), 7.42 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J=7.1 Hz, 1H), 5.08 (dd, J=12.9, 5.3 Hz, 1H), 4.28 (d, J=4.4 Hz, 2H), 3.74 (s, 2H), 3.70 (s, 2H), 3.05 (s, 2H), 3.01 (s, 2H), 3.05-2.87 (m, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.63 (s, 1H), 2.59-2.54 (m, 1H), 2.07-2.04 (m, 1H), 1.75 (s, 6H), 1.30 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₀H₃₈N₇O₆ [M+H]⁺: 712.2878, found, 712.2993.

Compound Example 93: Synthesis of 8-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164029)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151026) was used to prepare SIAIS164029 (yellow solid, 16.8 mg, 50%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.10 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.61 (t, J=7.5 Hz, 2H), 7.38 (s, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.82 (t, J=6.3 Hz, 1H), 5.05 (dd, J=12.7, 5.4 Hz, 1H), 3.68 (s, 2H), 3.63 (s, 2H), 3.61-3.56 (m, 2H), 2.96-2.94 (m, 4H), 2.92-2.83 (m, 1H), 2.78-2.71 (m, 4H), 2.65-2.52 (m, 2H), 2.03-2.01 (m, 1H), 1.74 (s, 6H), 1.28 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₁H₄₀N₇O₆ [M+H]⁺: 726.3035, found, 726.3166.

Compound Example 94: Synthesis of 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164024)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151019) was used to prepare SIAIS164024 (yellow solid, 23.6 mg, 69%). ¹H NMR (500 MHz, CDCl₃) δ 9.09 (s, 1H), 8.53 (d, J=8.2 Hz, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.58 (dd, J=8.2, 1.3 Hz, 1H), 7.51 (dd, J=8.5, 7.2 Hz, 1H), 7.14 (s, 1H), 7.10 (d, J=7.0 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.34 (s, 1H), 4.93 (dd, J=12.4, 5.4 Hz, 1H), 3.85 (s, 2H), 3.66 (s, 2H), 3.43 (s, 2H), 2.99 (d, J=4.5 Hz, 4H), 2.92-2.89 (m, 1H), 2.83-2.73 (m, 4H), 2.53 (t, J=6.9 Hz, 2H), 2.18-2.11 (m, 1H), 2.10-2.03 (m, 2H), 1.76 (s, 6H), 1.35 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₂H₄₂N₇O₆ [M+H]⁺: 740.3191, found, 740.3471.

Compound Example 95: Synthesis of 8-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164025)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151020) was used to prepare SIAIS164025 (yellow solid, 21 mg, 61%). ¹H NMR (500 MHz, CDCl₃) δ 9.49 (s, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.77 (d, J=0.5 Hz, 1H), 7.56 (dd, J=8.2, 1.3 Hz, 1H), 7.49 (dd, J=8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.25 (s, 1H), 4.90 (dd, J=12.4, 5.4 Hz, 1H), 3.86 (s, 2H), 3.69 (s, 2H), 3.32 (t, J=6.5 Hz, 2H), 3.07-2.95 (m, 4H), 2.89 (d, J=13.2 Hz, 1H), 2.83-2.71 (m, 4H), 2.49 (t, J=7.1 Hz, 2H), 2.16-2.12 (m, 1H), 1.86-1.82 (m, 2H), 1.78-1.75 (m, 8H), 1.35 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₆ [M+H]⁺: 754.3348, found, 754.3630.

Compound Example 96: Synthesis of 8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164026)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151027) was used to prepare SIAIS164026 (yellow solid, 20.4 mg, 58%). ¹H NMR (500 MHz, CDCl₃) δ 9.22 (s, 1H), 8.54 (d, J=8.2 Hz, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.58 (dd, J=8.2, 1.3 Hz, 1H), 7.49 (dd, J=8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.23 (s, 1H), 4.92 (dd, J=12.3, 5.4 Hz, 1H), 3.85 (s, 2H), 3.69 (s, 2H), 3.29 (t, J=6.8 Hz, 2H), 3.04-2.97 (m, 4H), 2.912-2.89 (m, 1H), 2.82-2.73 (m, 4H), 2.45 (t, J=7.5 Hz, 2H), 2.18-2.11 (m, 1H), 1.78-1.71 (m, 10H), 1.53-1.52 (m, 2H), 1.36 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₄H₄₆N₇O₆ [M+H]⁺: 768.3504, found, 768.3785.

Compound Example 97: Synthesis of -(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164030)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151086) was used to prepare SIAIS164030 (yellow solid, 19.4 mg, 54%). ¹H NMR (500 MHz, CDCl₃) δ 10.26 (s, 1H), 8.51 (d, J=8.2 Hz, 1H), 8.30 (s, 2H), 7.76 (d, J=0.5 Hz, 1H), 7.55 (dd, J=8.2, 1.3 Hz, 1H), 7.47 (dd, J=8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.06 (t, J=5.1 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.21 (s, 1H), 4.93 (dd, J=12.2, 5.5 Hz, 1H), 3.88 (s, 2H), 3.72 (s, 2H), 3.25 (t, J=7.0 Hz, 2H), 3.02 (dd, J=9.9, 4.8 Hz, 4H), 2.91-2.88 (m, 1H), 2.85-2.70 (m, 4H), 2.46 (t, J=7.5 Hz, 2H), 2.19-2.10 (m, 1H), 1.77-1.70 (m, 8H), 1.69-1.63 (m, 2H), 1.53-1.39 (m, 4H), 1.33 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₆ [M+H]⁺: 782.3661, found, 782.3818.

Compound Example 98: Synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164040)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151010) was used to prepare SIAIS164040 (white solid, 29.7 mg, 66%). ¹H NMR (500 MHz, CDCl₃) δ 10.26 (s, 1H), 8.94 (s, 1H), 8.51 (d, J=8.2 Hz, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.56 (dd, J=8.2, 1.3 Hz, 1H), 7.41-7.31 (m, 5H), 7.16 (s, 1H), 4.72 (t, J=8.1 Hz, 1H), 4.61-4.51 (m, 3H), 4.36 (dd, J=15.2, 5.4 Hz, 1H), 4.28 (s, 2H), 4.14 (d, J=11.7 Hz, 1H), 4.11-4.00 (m, 2H), 3.85-3.58 (m, 9H), 3.46-3.39 (m, 2H), 3.00 (s, 4H), 2.88 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 2.55 (s, 3H), 2.53-2.49 (m, 1H), 2.45 (t, J=8.2 Hz, 2H), 2.09-2.00 (m, 3H), 1.73 (d, J=3.4 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H), 0.97 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₃N₈O₈S [M+H]⁺: 971.4484, found, 971.4483.

Compound Example 99: Synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164036)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151002) was used to prepare SIAIS164036 (white solid, 16.1 mg, 35%). ¹H NMR (500 MHz, CDCl₃) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.55 (dd, J=8.2, 1.3 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.11 (s, 1H), 4.74 (t, J=8.2 Hz, 1H), 4.66 (dd, J=15.5, 6.8 Hz, 1H), 4.58 (s, 1H), 4.54 (d, J=8.4 Hz, 1H), 4.34 (dd, J=15.4, 5.2 Hz, 1H), 4.18 (d, J=11.4 Hz, 1H), 3.85-3.72 (m, 5H), 3.71-3.58 (m, 8H), 2.96-2.95 (m, 4H), 2.77-2.72 (m, 2H), 2.70 (t, J=6.3 Hz, 2H), 2.58 (s, 3H), 2.56-2.49 (m, 2H), 2.47-2.37 (m, 1H), 2.29-2.21 (m, 1H), 1.71 (d, J=3.1 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 0.97 (s, 9H). HRMS (ESI) calcd for C₅₅H₆₇N₈O₈S [M+H]⁺: 999.4797, found, 999.4847.

Compound Example 100: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164037)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151003) was used to prepare SIAIS164037 (white solid, 34.6 mg, 72%). ¹H NMR (500 MHz, CDCl₃) δ 10.62 (s, 1H), 9.10 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.28 (s, 1H), 7.78 (s, 1H), 7.54 (dd, J=8.2, 1.3 Hz, 1H), 7.46 (d, J=6.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.14 (s, 1H), 4.73 (t, J=8.3 Hz, 1H), 4.63 (dd, J=15.3, 6.8 Hz, 1H), 4.57-4.54 (m, 2H), 4.34 (dd, J=15.3, 5.1 Hz, 1H), 4.17 (d, J=11.4 Hz, 1H), 3.81-3.75 (m, 5H), 3.72-3.59 (m, 12H), 2.99-2.96 (m, 4H), 2.80-2.67 (m, 4H), 2.56 (s, 3H), 2.56-2.54 (m, 2H), 2.44-2.34 (m, 1H), 2.29-2.24 (m, 1H), 1.72 (d, J=2.7 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 0.99 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₁N₈O₉S [M+H]⁺: 1043.5059, found, 1043.5097.

Compound Example 101: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164038)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151008) was used to prepare SIAIS164038 (white solid, 32.5 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 10.78 (s, 1H), 9.08 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.53 (dd, J=8.2, 1.3 Hz, 1H), 7.39-7.37 (m, 3H), 7.34 (d, J=8.2 Hz, 2H), 7.15 (s, 1H), 4.73 (t, J=8.0 Hz, 1H), 4.65-4.56 (m, 2H), 4.54 (d, J=8.3 Hz, 1H), 4.35 (dd, J=15.3, 5.2 Hz, 1H), 4.14 (d, J=11.4 Hz, 1H), 3.82-3.81 (m, 4H), 3.70-3.67 (m, 5H), 3.63-3.61 (m, 12H), 3.00-2.96 (m, 4H), 2.78-2.71 (m, 4H), 2.54 (s, 3H), 2.52 (s, 2H), 2.41-2.39 (m, 1H), 2.28-2.27 (m, 1H), 1.73 (s, 6H), 1.32 (t, J=7.5 Hz, 3H), 0.98 (s, 9H). HRMS (ESI) calcd for C₅₉H₇₅N₈O₁₀S [M+H]⁺: 1087.5321, found, 1087.5342.

Compound Example 102: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164039)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151009) was used to prepare SIAIS164039 (white solid, 40.1 mg, 77%). ¹H NMR (500 MHz, CDCl₃) δ 10.84 (s, 1H), 9.03 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.54 (dd, J=8.2, 1.3 Hz, 1H), 7.37 (q, J=8.2 Hz, 5H), 7.22 (d, J=7.6 Hz, 1H), 7.17 (s, 1H), 4.74 (t, J=7.8 Hz, 1H), 4.63-4.59 (m, 2H), 4.54 (d, J=8.4 Hz, 1H), 4.36 (dd, J=15.2, 5.1 Hz, 1H), 4.14 (d, J=11.2 Hz, 1H), 3.83 (s, 4H), 3.75-3.68 (m, 4H), 3.65-3.61 (m, 16H), 3.01 (s, 2H), 2.97 (s, 2H), 2.79-2.76 (m, 2H), 2.75-2.71 (m, 3H), 2.54 (s, 3H), 2.53-2.52 (m, 2H), 2.44-2.43 (m, 1H), 2.26-2.25 (m, 1H), 1.75 (d, J=4.9 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H), 0.98 (s, 9H). HRMS (ESI) calcd for C₆₁H₇₉N₈O₁₁S [M+H]⁺: 1131.5584, found, 1131.5582.

Compound Example 103: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164093)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074011) was used to prepare SIAIS164093 (white solid, 21.2 mg, 67%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.99 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=9.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.41 (q, J=8.2 Hz, 5H), 4.55 (d, J=9.4 Hz, 1H), 4.43 (dd, J=14.3, 6.9 Hz, 2H), 4.36 (s, 1H), 4.22 (dd, J=16.0, 5.5 Hz, 1H), 3.64 (s, 7H), 2.99 (s, 2H), 2.93 (s, 2H), 2.76 (q, J=7.4 Hz, 2H), 2.65-2.54 (m, 3H), 2.45-2.42 (m, 4H), 2.09-1.99 (m, 1H), 1.96-1.86 (m, 1H), 1.74 (s, 6H), 1.29 (t, J=7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₁H₅₉N₈O₆S [M+H]⁺: 911.4273, found, 911.4539.

Compound Example 104: Synthesis of (2S,4R)-1-((S)-2-(5-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164094)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074012) was used to prepare SIAIS164094 (white solid, 16.7 mg, 52%). ¹H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 8.97 (s, 1H), 8.56 (t, J=5.9 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.45-7.35 (m, 5H), 4.56 (d, J=9.3 Hz, 1H), 4.42 (dd, J=16.5, 8.2 Hz, 2H), 4.35 (s, 1H), 4.21 (dd, J=15.9, 5.4 Hz, 1H), 3.73-3.59 (m, 7H), 2.98 (s, 2H), 2.92 (s, 2H), 2.75 (q, J=7.4 Hz, 2H), 2.43 (s, 3H), 2.36 (t, J=7.4 Hz, 2H), 2.33-2.19 (m, 2H), 2.06-2.02 (m, 1H), 1.93-1.88 (m, 1H), 1.75-1.72 (m, 8H), 1.28 (t, J=7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₁N₈O₆S [M+H]⁺: 925.4429, found, 925.4685.

Compound Example 105: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164095)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074013) was used to prepare SIAIS164095 (white solid, 19.6 mg, 60%). ¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.98 (s, 1H), 8.56 (t, J=5.8 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.44-7.36 (m, 5H), 4.56 (d, J=9.5 Hz, 1H), 4.49-4.39 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J=15.8, 5.4 Hz, 1H), 3.68-3.64 (m, 8H), 2.98 (s, 2H), 2.92 (s, 2H), 2.75 (q, J=7.4 Hz, 2H), 2.44 (s, 3H), 2.37 (s, 2H), 2.34-2.28 (m, 1H), 2.20-2.12 (m, 1H), 2.07-2.00 (m, 1H), 1.94-1.87 (m, 1H), 1.75 (s, 6H), 1.53 (d, J=6.8 Hz, 4H), 1.28 (t, J=7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₃N₈O₆S [M+H]⁺: 939.4586, found, 939.4864.

Compound Example 106: Synthesis of (2S,4R)-1-((S)-2-(7-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164096)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074014) was used to prepare SIAIS164096 (white solid, 21.6 mg, 66%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.98 (s, 1H), 8.56 (t, J=5.9 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.86 (d, J=9.3 Hz, 1H), 7.61 (dd, J=8.1, 1.2 Hz, 1H), 7.44-7.36 (m, 5H), 4.55 (d, J=9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J=15.9, 5.5 Hz, 1H), 3.69-3.62 (m, 7H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.37-2.32 (m, 2H), 2.31-2.24 (m, 1H), 2.18-2.11 (m, 1H), 2.06-2.00 (m, 1H), 1.94-1.87 (m, 1H), 1.75 (s, 6H), 1.55-1.49 (m, 4H), 1.32-1.25 (m, 5H), 0.93 (d, J=11.4 Hz, 9H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₆S [M+H]⁺: 953.4742, found, 953.4991.

Compound Example 107: Synthesis of (2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164097)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074015) was used to prepare SIAIS164097 (white solid, 22.6 mg, 68%). ¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.99 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.85 (d, J=9.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.45-7.36 (m, 5H), 4.55 (d, J=9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J=16.0, 5.3 Hz, 1H), 3.65-3.63 (m, 7H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.38-2.33 (m, 2H), 2.30-2.24 (m, 1H), 2.16-2.10 (m, 1H), 2.06-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.75 (s, 6H), 1.52-1.47 (m, 4H), 1.30-1.27 (m, 7H), 0.93 (s, 9H). HRMS (ESI) calcd for C₅₅H₆₇N₈O₆S [M+H]⁺: 967.4899, found, 967.5164.

Compound Example 108: Synthesis of (2S,4R)-1-((S)-2-(9-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164098)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074016) was used to prepare SIAIS164098 (white solid, 21.8 mg, 64%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.99 (s, 1H), 8.55 (t, J=6.0 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.61 (dd, J=8.1, 1.2 Hz, 1H), 7.44-7.36 (m, 5H), 4.55 (d, J=9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J=16.0, 5.6 Hz, 1H), 3.66-3.63 (m, 7H), 2.97 (s, 2H), 2.92 (s, 2H), 2.75 (q, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.35 (t, J=7.5 Hz, 2H), 2.31-2.23 (m, 1H), 2.16-2.08 (m, 1H), 2.05-2.00 (m, 1H), 1.92-1.87 (m, 1H), 1.75 (s, 6H), 1.52-1.46 (m, 4H), 1.30-1.27 (m, 9H), 0.92 (s, 9H). HRMS (ESI) calcd for C₅₆H₆₉N₈O₆S [M+H]⁺: 981.5055, found, 981.5349.

Compound Example 109: Synthesis of (2S,4R)-1-((S)-2-(10-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164099)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074019) was used to prepare SIAIS164099 (white solid, 20.1 mg, 59%). ¹H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 8.99 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.84 (d, J=9.4 Hz, 1H), 7.60 (dd, J=8.1, 1.2 Hz, 1H), 7.42-7.37 (m, 5H), 4.54 (d, J=9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J=15.9, 5.4 Hz, 1H), 3.69-3.63 (m, 7H), 2.97 (s, 2H), 2.92 (s, 2H), 2.75 (q, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.35 (t, J=7.4 Hz, 2H), 2.30-2.22 (m, 1H), 2.11 (dt, J=14.4, 6.5 Hz, 1H), 2.06-1.99 (m, 1H), 1.93-1.87 (m, 1H), 1.75 (s, 6H), 1.53-1.46 (m, 4H), 1.30-1.27 (m, 11H), 0.92 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₁N₈O₆S [M+H]⁺: 995.5212, found, 995.5518.

Compound Example 110: Synthesis of 4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide. (SIAIS164154)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS164119) was used to prepare SIAIS164154 (yellow solid, 9 mg, 49%). ¹H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 11.09 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.11 (t, J=5.3 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J=12.1, 5.6 Hz, 2H), 7.39 (s, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.75 (s, 1H), 5.05 (dd, J=12.8, 5.4 Hz, 1H), 3.63 (s, 4H), 3.29-3.21 (m, 2H), 2.98 (s, 2H), 2.92 (s, 2H), 2.88-2.85 (m, 1H), 2.75 (q, J=7.4 Hz, 2H), 2.66-2.51 (m, 6H), 2.35 (t, J=7.0 Hz, 2H), 2.05-1.98 (m, 1H), 1.75 (s, 6H), 1.29 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₄H₄₅N₈O₇ [M+H]⁺: 797.3406, found, 797.1339.

Compound Example 111: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164155)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS164128) was used to prepare SIAIS164155 (white solid, 9 mg, 38%). ¹H NMR (500 MHz, DMSO) δ 12.82 (s, 1H), 9.01 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J=10.0 Hz, 2H), 7.90 (s, 1H), 7.60 (dd, J=8.1, 1.2 Hz, 1H), 7.46-7.34 (m, 6H), 4.53 (d, J=9.3 Hz, 1H), 4.46-4.39 (m, 2H), 4.35 (s, 1H), 4.30 (t, J=7.1 Hz, 2H), 4.21 (dd, J=15.8, 5.4 Hz, 1H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J=7.4 Hz, 2H), 2.69-2.64 (m, 3H), 2.49-2.34 (m, 7H), 2.29-2.23 (m, 1H), 2.21-2.13 (m, 1H), 2.11-1.94 (m, 4H), 1.94-1.79 (m, 4H), 1.75 (s, 7H), 1.28 (t, J=7.5 Hz, 3H), 0.93 (s, 9H). HRMS (ESI) calcd for C₅₇H₆₈N₁₁O₆S [M+H]⁺: 1034.5069, found, 1034.2256.

Compound Example 112: Synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propenamide. (SIAIS219023)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151004) was used to prepare SIAIS219023 (yellow solid, 9.8 mg, 49%). ¹H NMR (500 MHz, MeOD) δ 8.41 (d, J=8.1 Hz, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.60-7.51 (m, 3H), 7.08 (d, J=8.5 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 5.06 (dd, J=12.5, 5.5 Hz, 1H), 4.14 (d, J=17.1 Hz, 1H), 3.96 (t, J=11.3 Hz, 1H), 3.80-3.73 (m, 2H), 3.69-3.61 (m, 6H), 3.50 (t, J=5.2 Hz, 2H), 3.20 (d, J=27.6 Hz, 4H), 2.89-2.69 (m, 6H), 2.48 (t, J=6.1 Hz, 2H), 2.10 (d, J=4.6 Hz, 2H), 1.88-1.75 (m, 8H), 1.37-1.29 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₀N₇O₈ [M+H]⁺: 828.3715, found, 828.3762.

Compound Example 113: Synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide. (SIAIS219024)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151006) was used to prepare SIAIS219024 (yellow solid, 11.2 mg, 51%). ¹H NMR (500 MHz, MeOD) δ 8.41 (d, J=8.1 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 2H), 7.58 (dd, J=8.2, 1.4 Hz, 1H), 7.50 (dd, J=8.5, 7.1 Hz, 1H), 7.02 (dd, J=14.9, 7.8 Hz, 2H), 5.06 (dd, J=12.6, 5.5 Hz, 1H), 4.10 (t, J=10.9 Hz, 1H), 3.76 (t, J=6.1 Hz, 2H), 3.69-3.54 (m, 14H), 3.47-3.41 (m, 2H), 3.17 (s, 4H), 2.94-2.83 (m, 3H), 2.77-2.67 (m, 2H), 2.49 (t, J=6.0 Hz, 2H), 2.24 (d, J=11.8 Hz, 2H), 2.14-2.00 (m, 3H), 1.83 (s, 4H), 1.42 (t, J=7.5 Hz, 3H), 1.35-1.24 (m, 2H). HRMS (ESI) calcd for C₅₀H₅₈N₇O₁₀ [M+H]⁺: 916.4240, found, 916.4319.

Compound Example 114: Synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide. (SIAIS219001)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151025) was used to prepare SIAIS219001 (yellow solid, 7.4 mg, 42%). ¹H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 11.11 (s, 1H), 8.31 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.63-7.59 (m, 2H), 7.37 (s, 1H), 7.08 (d, J=6.7 Hz, 1H), 6.97-6.93 (m, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.07 (dd, J=12.8, 5.4 Hz, 1H), 3.97 (s, 4H), 3.82 (s, 2H), 2.86-2.84 (m, 3H), 2.70 (d, J=7.4 Hz, 4H), 1.90 (s, 2H), 1.75 (s, 6H), 1.66 (s, 2H), 1.27 (t, J=7.4 Hz, 3H). HRMS (ESI) calcd for C₄₁H₄₀N₇O₆ [M+H]⁺: 726.3035, found, 726.3045.

Compound Example 115: Synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamide. (SIAIS219010)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151019) was used to prepare SIAIS219010 (yellow solid, 7.2 mg, 40%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.10 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.63-7.58 (m, 2H), 7.36 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.64 (t, J=6.1 Hz, 1H), 5.06 (dd, J=12.7, 5.4 Hz, 1H), 3.77 (s, 1H), 3.15 (d, J=12.3 Hz, 2H), 2.88-2.83 (m, 3H), 2.69 (q, J=7.4 Hz, 2H), 2.63-2.58 (m, 2H), 2.19 (t, J=7.2 Hz, 2H), 2.05-2.00 (m, 1H), 1.89 (d, J=10.3 Hz, 2H), 1.85-1.79 (m, 2H), 1.75 (s, 6H), 1.62-1.53 (m, 2H), 1.28-1.24 (m, 5H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₆ [M+H]⁺: 754.3348, found, 754.3170.

Compound Example 116: Synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide. (SIAIS219011)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151027) was used to prepare SIAIS219011 (yellow solid, 8.8 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 11.13 (s, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.65-7.59 (m, 2H), 7.37 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.65 (t, J=6.1 Hz, 1H), 5.08 (dd, J=12.7, 5.4 Hz, 1H), 3.78 (s, 1H), 3.17 (d, J=12.3 Hz, 2H), 2.88-2.85 (m, 3H), 2.70 (q, J=7.4 Hz, 2H), 2.61-2.59 (m, 2H), 2.21 (t, J=7.2 Hz, 2H), 2.06-2.01 (m, 4H), 1.90 (d, J=10.3 Hz, 2H), 1.86-1.79 (m, 2H), 1.77 (s, 6H), 1.62-1.54 (m, 2H), 1.29-1.27 (m, 6H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₆ [M+H]⁺: 782.3661, found, 782.3465.

Compound Example 117: Synthesis of N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide. (SIAIS219020)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS074013) was used to prepare SIAIS219020 (white solid, 9.9 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.81 (s, 1H), 8.43-8.39 (m, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.88 (s, 1H), 7.58-7.49 (m, 5H), 4.64 (s, 1H), 4.60-4.49 (m, 3H), 4.41 (d, J=15.7 Hz, 1H), 4.08 (s, 1H), 3.92 (d, J=11.1 Hz, 1H), 3.81 (dd, J=11.0, 3.9 Hz, 1H), 3.61 (d, J=9.8 Hz, 2H), 3.54 (s, 2H), 2.94-2.86 (m, 2H), 2.58 (s, 3H), 2.39-2.19 (m, 8H), 2.08-2.05 (m, 2H), 1.85 (s, 6H), 1.67-1.66 (m, 4H), 1.41 (t, J=7.5 Hz, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₆S [M+H]⁺: 953.4742, found, 953.4074.

Compound Example 118: Synthesis of N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide. (SIAIS219021)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS074019) was used to prepare SIAIS219021 (white solid, 11.2 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 9.60 (s, 1H), 8.41 (d, J=8.2 Hz, 1H), 8.26 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.57-7.47 (m, 5H), 4.64 (s, 1H), 4.59-4.52 (m, 2H), 4.50 (s, 1H), 4.39 (d, J=15.7 Hz, 1H), 3.98 (s, 1H), 3.91 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.9 Hz, 1H), 3.45-3.44 (m, 2H), 3.29-3.22 (m, 2H), 2.86 (q, J=7.4 Hz, 2H), 2.55 (d, J=2.9 Hz, 3H), 2.29-2.21 (m, 5H), 2.14-2.06 (m, 3H), 1.89 (d, J=10.8 Hz, 2H), 1.83 (s, 6H), 1.63 (d, J=6.4 Hz, 4H), 1.39-1.34 (m, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₃N₈O₆S [M+H]⁺: 1009.5368, found, 1009.4649.

Compound Example 119: Synthesis of 8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219018)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151004) was used to prepare SIAIS219018 (yellow solid, 8.8 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.81 (s, 1H), 11.10 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.06 (d, J=3.0 Hz, 1H), 8.01 (s, 1H), 7.62-7.58 (m, 2H), 7.35 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.05 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 5.06 (dd, J=12.7, 5.4 Hz, 1H), 4.51 (d, J=11.5 Hz, 1H), 4.11 (d, J=15.1 Hz, 1H), 3.67-3.46 (m, 14H), 3.33-3.24 (m, 6H), 3.12-3.05 (m, 1H), 2.92-2.78 (m, 3H), 2.73-2.68 (m, 2H), 2.66-2.53 (m, 3H), 2.25-2.16 (m, 2H), 2.06-1.99 (m, 1H), 1.96-1.85 (m, 2H), 1.76 (d, J=2.0 Hz, 6H), 1.30-1.26 (m, 3H). HRMS (ESI) calcd for C₅₀H₅₇N₈O₈ [M+H]⁺: 897.4294, found, 897.3670.

Compound Example 120: Synthesis of 8-(4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219019)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151006) was used to prepare SIAIS219019 (yellow solid, 10.1 mg, 49%). ¹H NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 11.09 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.06 (d, J=3.0 Hz, 1H), 8.00 (s, 1H), 7.61-7.56 (m, 2H), 7.36 (s, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.60 (s, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 4.51 (d, J=13.5 Hz, 1H), 4.12 (d, J=13.9 Hz, 1H), 3.66-3.60 (m, 4H), 3.60-3.46 (m, 20H), 3.30 (s, 4H), 3.12 (t, J=12.9 Hz, 2H), 2.91-2.78 (m, 3H), 2.73-2.68 (m, 3H), 2.26-2.19 (m, 2H), 2.3-2.002 (m, 1H), 1.95-1.87 (m, 2H), 1.76 (s, 6H), 1.30-1.26 (m, 3H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₁₀ [M+H]⁺: 985.4818, found, 985.4897.

Compound Example 121: Synthesis of 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS184194)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151025) was used to prepare SIAIS184194 (yellow solid, 6.2 mg, 37%). ¹H NMR (500 MHz, DMSO) δ 12.78 (s, 1H), 11.11 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.65-7.59 (m, 2H), 7.37 (s, 1H), 7.12 (dd, J=14.8, 7.8 Hz, 2H), 7.04 (s, 1H), 5.08 (dd, J=12.5, 5.4 Hz, 1H), 4.58-4.52 (m, 1H), 4.28-4.21 (m, 1H), 3.61 (s, 2H), 3.48 (d, J=5.2 Hz, 3H), 3.44-3.40 (m, 8H), 2.83 (s, 3H), 2.72 (d, J=7.5 Hz, 2H), 2.28-2.18 (m, 2H), 2.08-2.01 (m, 1H), 1.95-1.88 (m, 2H), 1.76 (s, 6H), 1.29 (t, J=7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₇N₈O₆ [M+H]⁺: 795.3613, found, 795.3622.

Compound Example 122: Synthesis of 8-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219003)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151019) was used to prepare SIAIS219003 (yellow solid, 6.6 mg, 38%). ¹H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 11.09 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.33 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.66 (s, 1H), 5.06 (dd, J=12.8, 5.6 Hz, 1H), 3.26-3.18 (m, 6H), 2.78-2.68 (m, 10H), 2.40 (s, 4H), 2.07-1.99 (m, 2H), 1.89-1.78 (m, 6H), 1.75 (s, 6H), 1.61 (t, J=10.4 Hz, 2H), 1.27 (t, J=11.8 Hz, 5H). HRMS (ESI) calcd for C₄₇H₅₁N₈O₆ [M+H]⁺: 823.3926, found, 823.5145.

Compound Example 123: Synthesis of 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219004)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151027) was used to prepare SIAIS219004 (yellow solid, 7.1 mg, 40%). ¹H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 11.08 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.58 (s, 1H), 5.07 (dd, J=12.8, 5.6 Hz, 1H), 3.24-3.13 (m, 6H), 2.75-2.65 (m, 10H), 2.36 (s, 4H), 2.05-1.97 (m, 2H), 1.86-1.77 (m, 6H), 1.73 (s, 6H), 1.60 (t, J=10.4 Hz, 2H), 1.25-1.20 (m, 9H). HRMS (ESI) calcd for C₄₉H₅₅N₈O₆ [M+H]⁺:851.4239, found, 851.5517.

Compound Example 124: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS219015)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS074013) was used to prepare SIAIS219015 (yellow solid, 10.2 mg, 48%). ¹H NMR (500 MHz, DMSO) δ 12.79 (s, 1H), 10.63 (s, 1H), 8.98 (s, 1H), 8.57 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.62-7.59 (m, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.40-7.34 (m, 3H), 4.57-4.50 (m, 2H), 4.47-4.40 (m, 2H), 4.35 (s, 1H), 4.22 (d, J=11.5 Hz, 1H), 4.09 (d, J=16.2 Hz, 1H), 3.70-3.62 (m, 2H), 3.54 (d, J=16.2 Hz, 3H), 3.14 (d, J=9.2 Hz, 1H), 3.02 (d, J=18.4 Hz, 2H), 2.81 (t, J=10.6 Hz, 2H), 2.74-2.68 (m, 2H), 2.44 (s, 3H), 2.40-2.35 (m, 2H), 2.32-2.25 (m, 1H), 2.19 (t, J=14.0 Hz, 3H), 2.04-1.99 (m, 2H), 1.93-1.88 (m, 3H), 1.76 (s, 6H), 1.55-1.46 (m, 4H), 1.30-1.23 (m, 5H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₂N₉O₆S [M+H]⁺: 1022.5321, found, 1022.4607.

Compound Example 125: Synthesis of (2S,4R)-1-((S)-2-(10-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS219016)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS074019) was used to prepare SIAIS219016 (yellow solid, 9.8 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.86 (s, 1H), 8.40 (d, J=8.1 Hz, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.57-7.54 (m, 5H), 7.43 (s, 1H), 4.64 (s, 1H), 4.59-4.53 (m, 3H), 4.41 (d, J=15.7 Hz, 1H), 4.27 (s, 1H), 3.91 (d, J=11.1 Hz, 1H), 3.81 (dd, J=11.0, 3.8 Hz, 1H), 3.72 (s, 2H), 3.43 (d, J=11.2 Hz, 3H), 3.15 (d, J=12.9 Hz, 2H), 2.99 (t, J=11.4 Hz, 2H), 2.81 (q, J=7.5 Hz, 2H), 2.59 (s, 3H), 2.47 (t, J=7.4 Hz, 2H), 2.39-2.20 (m, 6H), 2.10-2.04 (m, 4H), 1.80 (s, 6H), 1.62 (d, J=6.2 Hz, 4H), 1.35 (t, J=7.4 Hz, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₀N₉O₆S [M+H]⁺:1078.5947, found, 1078.5193.

Compound Example 126: Synthesis of 4-((2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151031)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151001) was used to prepare SIAIS151031 (yellow solid, 20.8 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J=7.8 Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J=8.0, 1.5 Hz, 1H), 7.76 (s, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.07 (dd, J=8.4, 7.0 Hz, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 5.00-4.94 (m, 1H), 4.70 (d, J=13.0 Hz, 1H), 4.58 (s, 1H), 4.56-4.50 (m, 1H), 4.16 (d, J=13.4 Hz, 1H), 3.90-3.77 (m, 2H), 3.73-3.70 (m, 2H), 3.52-3.49 (m, 2H), 3.22-3.13 (m, 1H), 3.00-2.93 (m, 1H), 2.81-2.59 (m, 6H), 2.13 (d, J=1.0 Hz, 3H), 2.03-1.95 (m, 1H), 1.76 (d, J=13.1 Hz, 2H), 1.67-1.54 (m, 2H), 1.28-1.25 (m, 12H). HRMS (ESI) calcd for C₄₆H₅₄ClN₈O₉S [M+H]⁺: 929.3418, found, 929.2502.

Compound Example 127: Synthesis of 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151023)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151004) was used to prepare SIAIS151023 (yellow solid, 32.8 mg, 94%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J=8.3 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.74 (s, 1H), 7.69-7.66 (m, 1H), 7.51-7.47 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.02 (dd, J=8.5, 4.0 Hz, 1H), 7.00 (d, J=7.0 Hz, 2H), 6.79 (s, 1H), 5.01 (dd, J=12.5, 5.5 Hz, 1H), 4.69 (d, J=13.1 Hz, 1H), 4.59-4.54 (m, 1H), 4.12 (d, J=13.0 Hz, 1H), 3.81-3.74 (m, 2H), 3.71-3.60 (m, 6H), 3.45-3.41 (m, 2H), 3.36-3.32 (m, 1H), 3.21-3.13 (m, 1H), 2.99-2.93 (m, 1H), 2.84-2.64 (m, 5H), 2.63-2.55 (m, 1H), 2.13 (s, 3H), 2.07-2.03 (m, 1H), 1.79-1.71 (m, 2H), 1.67-1.52 (m, 2H), 1.31-1.28 (m, 6H), 1.26 (d, J=6.8 Hz, 6H). HRMS (ESI) calcd for C₄₈H₅₈ClN₈O₁₀S [M+H]⁺: 973.3680, found, 973.3685.

Compound Example 128: Synthesis of 4-((2-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy) ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151028)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151005) was used to prepare SIAIS151028 (yellow solid, 32.4 mg, 89%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.76 (s, 1H), 7.70-7.64 (m, 1H), 7.50 (dd, J=8.4, 7.2 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.02 (t, J=7.2 Hz, 2H), 6.80 (s, 1H), 5.02 (dd, J=12.5, 5.5 Hz, 1H), 4.70 (d, J=13.0 Hz, 1H), 4.61-4.54 (m, 1H), 4.14 (d, J=11.9 Hz, 1H), 3.82-3.71 (m, 2H), 3.67-3.59 (m, 10H), 3.43 (t, J=5.4 Hz, 2H), 3.35-3.31 (m, 1H), 3.22-3.16 (m, 1H), 3.01-2.95 (m, 1H), 2.83 (s, 1H), 2.81-2.67 (m, 4H), 2.63-2.56 (m, 1H), 2.15 (s, 3H), 2.10-2.04 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.52 (m, 2H), 1.29 (t, J=6.0 Hz, 6H), 1.25 (d, J=6.8 Hz, 6H). HRMS (ESI) calcd for C₅₀H₆₂ClN₈₀O₁₁S [M+H]⁺: 1017.3942, found, 1017.3457.

Compound Example 129: Synthesis of 4-((18-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151029)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151007) was used to prepare SIAIS151029 (yellow solid, 31.6 mg, 80%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 7.93-7.90 (m, 1H), 7.76 (s, 1H), 7.68-7.64 (m, 1H), 7.51 (dd, J=8.5, 7.1 Hz, 1H), 7.38-7.34 (m, 1H), 7.03 (dd, J=12.8, 7.8 Hz, 2H), 6.80 (s, 1H), 5.02 (dd, J=12.6, 5.5 Hz, 1H), 4.70 (d, J=13.4 Hz, 1H), 4.61-4.55 (m, 2H), 4.15 (d, J=14.0 Hz, 1H), 3.79-3.74 (m, 2H), 3.68 (t, J=5.3 Hz, 2H), 3.62-3.55 (m, 16H), 3.46-3.43 (m, 2H), 3.24-3.18 (m, 1H), 3.04-2.94 (m, 1H), 2.83-2.61 (m, 6H), 2.15 (s, 3H), 2.10-2.04 (m, 1H), 1.82-1.76 (m, 2H), 1.69-1.53 (m, 2H), 1.30 (t, J=6.1 Hz, 6H), 1.26 (s, 3H), 1.24 (s, 3H). HRMS (ESI) calcd for C₅₄H₇₀ClN₈O₁₃S [M+H]⁺: 1105.4466, found, 1105.3969.

Compound Example 130: Synthesis of 4-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151037)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151025) was used to prepare SIAIS151037 (yellow solid, 20.1 mg, 64%). ¹H NMR (500 MHz, DMSO) δ 11.11 (s, 1H), 9.46 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.84 (dd, J=8.0, 1.6 Hz, 1H), 7.66-7.59 (m, 2H), 7.53 (s, 1H), 7.40-7.33 (m, 1H), 7.20-7.15 (m, 2H), 7.08 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 5.08 (dd, J=12.9, 5.4 Hz, 1H), 4.60-4.54 (m, 2H), 4.35-4.13 (m, 2H), 4.05 (d, J=13.0 Hz, 1H), 3.48-3.40 (m, 1H), 3.24-3.14 (m, 1H), 3.01-2.85 (m, 2H), 2.77 (t, J=12.1 Hz, 1H), 2.63-2.52 (m, 2H), 2.17 (s, 3H), 2.08-2.00 (m, 1H), 1.74-1.71 (m, 3H), 1.59-1.48 (m, 1H), 1.20-1.15 (m, 12H). HRMS (ESI) calcd for C₄₃H₄₈ClN₈₀S [M+H]⁺: 871.2999, found, 871.0255.

Compound Example 131: Synthesis of 4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151034)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151026) was used to prepare SIAIS151034 (yellow solid, 27.1 mg, 85%). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.45 (s, 1H), 8.46 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.83 (dd, J=8.0, 1.5 Hz, 1H), 7.66-7.56 (m, 2H), 7.52 (s, 1H), 7.40-7.30 (m, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.87-6.77 (m, 2H), 5.04 (dd, J=12.8, 5.5 Hz, 1H), 4.65-4.52 (m, 2H), 3.98 (d, J=12.6 Hz, 1H), 3.57 (dd, J=12.4, 6.1 Hz, 2H), 3.46-3.41 (m, 1H), 3.11 (t, J=11.8 Hz, 1H), 2.96-2.83 (m, 2H), 2.71 (t, J=6.3 Hz, 2H), 2.68-2.52 (m, 3H), 2.14 (s, 3H), 2.05-1.97 (m, 1H), 1.71-1.67 (m, 2H), 1.64-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.21-1.13 (m, 12H). HRMS (ESI) calcd for C₄₄H₅₀ClN₈O₈S [M+H]⁺: 885.3155, found, 885.2667.

Compound Example 132: Synthesis of 4-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151035)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151019) was used to prepare SIAIS151035 (yellow solid, 21.5 mg, 67%). ¹H NMR (500 MHz, MeOD) δ 8.46 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (s, 1H), 7.70-7.64 (m, 1H), 7.56 (dd, J=8.5, 7.1 Hz, 1H), 7.39-7.35 (m, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.79 (s, 1H), 5.05-5.01 (m, 1H), 4.71 (d, J=11.6 Hz, 1H), 4.59-4.52 (m, 1H), 4.09 (d, J=12.5 Hz, 1H), 3.47-3.41 (m, 2H), 3.36-3.33 (m, 1H), 3.24-3.16 (m, 1H), 3.01-2.95 (m, 1H), 2.86-2.78 (m, 1H), 2.77-2.66 (m, 3H), 2.64-2.49 (m, 2H), 2.15 (s, 3H), 2.10-1.96 (m, 3H), 1.79 (d, J=13.1 Hz, 2H), 1.63-1.49 (m, 2H), 1.29 (d, J=6.0 Hz, 6H), 1.26 (d, J=6.8 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₂ClN₈O₈S [M+H]⁺: 899.3312, found, 899.0450.

Compound Example 133: Synthesis of 4-((5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151036)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151020) was used to prepare SIAIS151036 (yellow solid, 31.5 mg, 96%). ¹H NMR (500 MHz, MeOD) δ 8.46 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.77 (s, 1H), 7.74-7.66 (m, 1H), 7.55 (dd, J=8.5, 7.2 Hz, 1H), 7.39-7.35 (m, 1H), 7.08 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.79 (s, 1H), 5.03-4.95 (m, 1H), 4.69 (d, J=11.6 Hz, 1H), 4.61-4.53 (m, 1H), 4.08-4.04 (m, 1H), 3.46-3.32 (m, 3H), 3.24-3.16 (m, 1H), 3.01-2.97 (m, 1H), 2.82-2.61 (m, 4H), 2.57-2.44 (m, 2H), 2.15 (s, 3H), 2.05-1.99 (m, 1H), 1.82-1.72 (m, 6H), 1.65-1.51 (m, 2H), 1.31-1.27 (m, 6H), 1.26 (d, J=6.8 Hz, 6H). HRMS (ESI) calcd for C₄₆H₅₄ClN₈₀S [M+H]⁺: 913.3468, found, 913.0576.

Compound Example 134: Synthesis of 4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151043)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151027) was used to prepare SIAIS151043 (yellow solid, 26.3 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 8.26 (d, J=8.3 Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J=8.0, 1.4 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.45 (dd, J=8.5, 7.1 Hz, 1H), 7.40-7.36 (m, 2H), 6.95 (dd, J=13.9, 7.8 Hz, 2H), 6.76 (d, J=2.2 Hz, 1H), 4.95-4.90 (m, 1H), 4.63-4.59 (m, 1H), 4.52-4.47 (m, 1H), 4.00 (d, J=13.1 Hz, 1H), 3.27 (t, J=6.9 Hz, 3H), 3.14-3.08 (m, 1H), 2.95-2.89 (m, 1H), 2.75-2.54 (m, 4H), 2.38 (t, J=7.4 Hz, 2H), 2.09 (s, 3H), 2.01-1.93 (m, 1H), 1.74-1.66 (m, 2H), 1.66-1.58 (m, 4H), 1.55-1.38 (m, 4H), 1.17-1.15 (m, 12H). HRMS (ESI) calcd for C₄₇H₅₆ClN₈₀S [M+H]⁺: 927.3625, found, 927.0642.

Compound Example 135: Synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151042)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151010) was used to prepare SIAIS151042 (white solid, 36.8 mg, 91%). ¹H NMR (500 MHz, MeOD) δ 8.91 (d, J=1.6 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.99 (dd, J=8.0, 1.4 Hz, 1H), 7.75-7.69 (m, 1H), 7.53-7.49 (m, 1H), 7.47-7.34 (m, 5H), 6.86 (d, J=6.2 Hz, 1H), 4.72-4.53 (m, 4H), 4.51-4.31 (m, 5H), 4.13-4.01 (m, 3H), 3.88-3.86 (m, 1H), 3.83-3.69 (m, 5H), 3.39-3.34 (m, 1H), 3.24-3.16 (m, 1H), 3.07-2.97 (m, 1H), 2.79-2.71 (m, 1H), 2.47-2.45 (m, 3H), 2.26-2.14 (m, 1H), 2.18 (s, 3H), 2.12-2.04 (m, 1H), 1.82-1.77 (m, 2H), 1.73-1.53 (m, 2H), 1.27-1.24 (m, 12H), 1.05 (d, J=4.5 Hz, 9H). HRMS (ESI) calcd for C₅₆H₇₃ClN₉O₁₀S₂[M+H]⁺: 1130.4605, found, 1130.0737.

Compound Example 136: Synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151038)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151002) was used to prepare SIAIS151038 (white solid, 39.4 mg, 95%). ¹H NMR (500 MHz, MeOD) δ 8.92 (d, J=2.4 Hz, 1H), 8.32 (d, J=7.2 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J=8.0, 1.5 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.48-7.35 (m, 5H), 6.87 (s, 1H), 4.72-4.69 (m, 1H), 4.67-4.64 (m, 1H), 4.64-4.47 (m, 4H), 4.35 (d, J=15.3 Hz, 1H), 4.16 (d, J=12.2 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.82-3.67 (m, 5H), 3.66-3.60 (m, 4H), 3.40-3.35 (m, 1H), 3.25-3.19 (m, 1H), 3.03 (t, J=10.9 Hz, 1H), 2.77-2.65 (m, 3H), 2.58-2.52 (m, 1H), 2.50-2.43 (m, 4H), 2.24-2.18 (m, 1H), 2.20 (s, 3H), 2.11-2.05 (m, 1H), 1.86-1.75 (m, 2H), 1.71-1.52 (m, 2H), 1.28-1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₇ClN₉O₁₀S₂ [M+H]⁺: 1158.4918, found, 1158.4604.

Compound Example 137: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151039)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151003) was used to prepare SIAIS151039 (white solid, 40.2 mg, 93%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.32 (d, J=7.6 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J=8.0, 1.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.54-7.49 (m, 1H), 7.48-7.36 (m, 5H), 6.88 (s, 1H), 4.74-3.70 (m, 1H), 4.66-4.47 (m, 5H), 4.35 (d, J=15.5 Hz, 1H), 4.16 (d, J=12.6 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.81-3.76 (m, 3H), 3.74-3.67 (m, 2H), 3.63-3.58 (m, 8H), 3.40-3.35 (m, 1H), 3.23 (t, J=12.9 Hz, 1H), 3.06-3.00 (m, 1H), 2.78-2.64 (m, 3H), 2.59-2.53 (m, 1H), 2.50-2.42 (m, 4H), 2.25-2.17 (m, 1H), 2.20 (s, 3H), 2.11-2.05 (m, 1H), 1.80 (t, J=15.3 Hz, 2H), 1.73-1.53 (m, 2H), 1.28-1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₁ClN₉O₁₁S₂[M+H]⁺: 1202.5180, found, 1203.4829.

Compound Example 138: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151040)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151008) was used to prepare SIAIS151040 (white solid, 34.3 mg, 77%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.48-7.41 (m, 4H), 7.36 (s, 1H), 6.89 (s, 1H), 4.72 (d, J=13.5 Hz, 1H), 4.65-4.47 (m, 5H), 4.35 (d, J=15.5 Hz, 1H), 4.17 (d, J=13.7 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.81-3.76 (m, 3H), 3.74-3.67 (m, 2H), 3.63-3.56 (m, 14H), 3.41-3.35 (m, 1H), 3.23 (t, J=12.3 Hz, 1H), 3.07-3.01 (m, 1H), 2.80-2.64 (m, 3H), 2.59-2.53 (m, 1H), 2.49-2.45 (m, 4H), 2.25-2.18 (m, 1H), 2.20 (s, 3H), 2.11-2.05 (m, 1H), 1.80 (t, J=15.2 Hz, 2H), 1.74-1.55 (m, 2H), 1.28-1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₅ClN₉O₁₂S₂[M+H]⁺: 1246.5442, found, 1246.5029.

Compound Example 139: Synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151041)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151009) was used to prepare SIAIS151041 (white solid, 40 mg, 86%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.32 (d, J=7.5 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.53-7.49 (m, 1H), 7.43 (ddd, J=19.0, 15.8, 9.5 Hz, 5H), 6.89 (s, 1H), 4.72 (d, J=13.5 Hz, 1H), 4.66-4.48 (m, 5H), 4.37-4.33 (m, 1H), 4.17 (d, J=13.5 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.84-3.76 (m, 3H), 3.75-3.67 (m, 2H), 3.63-3.58 (m, 16H), 3.40-3.35 (m, 1H), 3.23 (t, J=12.0 Hz, 1H), 3.07-3.01 (m, 1H), 2.78-2.65 (m, 3H), 2.61-2.52 (m, 1H), 2.50-2.42 (m, 1H), 2.47 (s, 3H), 2.24-2.18 (m, 4H), 2.10-2.05 (m, 1H), 1.81 (t, J=15.2 Hz, 2H), 1.74-1.52 (m, 2H), 1.28-1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₄H₈₉ClN₉O₁₃S₂[M+H]⁺: 1290.5704, found, 1290.5117.

Compound Example 140: Synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074017)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074011) was used to prepare SIAIS074017 (white solid, 72 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 8.86 (d, J=1.7 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (s, 1H), 7.69-7.64 (m, 1H), 7.48-7.44 (m, 2H), 7.42-7.40 (m, 2H), 7.38-7.35 (m, 1H), 6.80 (d, J=7.1 Hz, 1H), 4.68 (d, J=11.6 Hz, 1H), 4.63 (d, J=7.4 Hz, 1H), 4.61-4.53 (m, 3H), 4.53-4.44 (m, 2H), 4.36 (dd, J=15.4, 4.3 Hz, 1H), 4.12 (d, J=13.5 Hz, 1H), 3.90 (d, J=11.1 Hz, 1H), 3.80 (dd, J=11.0, 3.8 Hz, 1H), 3.24-3.19 (m, 1H), 3.03-2.97 (m, 1H), 2.80-2.68 (m, 3H), 2.67-2.53 (m, 2H), 2.47 (d, J=3.0 Hz, 3H), 2.25-2.18 (m, 1H), 2.16 (s, 3H), 2.11-2.05 (m, 1H), 1.83-1.76 (m, 2H), 1.71-1.63 (m, 1H), 1.59-1.51 (m, 1H), 1.32-1.29 (m, 6H), 1.25 (d, J=6.8 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₄H₆₉ClN₉O₈S₂ ⁺ [M+H]⁺: 1070.4394; found, 1070.4352.

Compound Example 141: Synthesis of (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074018)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074012) was used to prepare SIAIS074018 (white solid, 25.2 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 10.63-10.18 (m, 1H), 9.28-8.52 (m, 3H), 8.42 (d, J=7.9 Hz, 1H), 8.09-7.86 (m, 1H), 7.59-7.43 (m, 1H), 7.35 (t, J=15.5 Hz, 6H), 7.13 (s, 1H), 6.73 (d, J=14.8 Hz, 1H), 6.27 (s, 1H), 4.76 (s, 1H), 4.52 (d, J=24.2 Hz, 3H), 4.34 (d, J=13.3 Hz, 1H), 4.06 (d, J=72.7 Hz, 2H), 3.75-3.45 (m, 1H), 3.28-3.08 (m, 2H), 2.88 (d, J=43.8 Hz, 2H), 2.67 (s, 3H), 2.60-2.25 (m, 7H), 2.19 (s, 4H), 2.10-1.72 (m, 4H), 1.57 (s, 2H), 1.32 (dd, J=42.6, 36.2 Hz, 13H), 1.11-0.82 (m, 9H). HRMS (ESI) calcd for C₅₅H₇₁ClN₉O₈S₂ ⁺ [M+H]⁺: 1084.4550; found, 1084.4549.

Compound Example 142: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074021)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074013) was used to prepare SIAIS074021 (white solid, 27.3 mg, 69%). ¹H NMR (500 MHz, CDCl₃) δ 10.27 (s, 1H), 10.23-10.07 (m, 1H), 8.83 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 7.99 (s, 1H), 7.91 (dd, J=7.9, 1.4 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.40 (dd, J=15.4, 6.9 Hz, 1H), 7.38-7.28 (m, 4H), 6.73 (d, J=3.8 Hz, 1H), 6.42 (dd, J=25.8, 8.5 Hz, 1H), 5.35 (t, J=4.8 Hz, 1H), 4.88-4.70 (m, 2H), 4.59 (dd, J=15.0, 6.7 Hz, 1H), 4.51 (dd, J=11.9, 5.4 Hz, 2H), 4.34 (dd, J=14.9, 5.1 Hz, 1H), 4.13 (d, J=11.8 Hz, 1H), 4.00 (d, J=12.3 Hz, 1H), 3.80-3.42 (m, 6H), 3.26-3.09 (m, 2H), 2.92 (t, J=12.0 Hz, 1H), 2.65 (s, 1H), 2.57 (ddd, J=16.5, 8.1, 4.0 Hz, 1H), 2.53 (s, 2H), 2.39 (s, 1H), 2.34-2.21 (m, 2H), 2.21-2.12 (m, 3H), 2.04-1.97 (m, 1H), 1.88-1.77 (m, 2H), 1.75-1.47 (m, 5H), 1.34-1.23 (m, 12H), 1.01-0.75 (m, 7H). HRMS (ESI) calcd for C₅₆H₇₃ClN₉O₈S₂ ⁺ [M+H]⁺: 1098.4707; found, 1098.6188.

Compound Example 143: Synthesis of (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074022)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074014) was used to prepare SIAIS074022 (white solid, 29.5 mg, 74%). ¹H NMR (500 MHz, CDCl₃) δ 10.11 (s, 1H), 9.63 (s, 1H), 8.76 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.92 (dd, J=7.9, 1.5 Hz, 1H), 7.58 (s, 1H), 7.45 (t, J=7.3 Hz, 1H), 7.40-7.32 (m, 4H), 7.29 (t, J=7.7 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 4.77 (dd, J=19.4, 11.3 Hz, 2H), 4.64-4.46 (m, 4H), 4.34 (dd, J=15.0, 5.1 Hz, 2H), 4.05 (dd, J=56.9, 11.8 Hz, 3H), 3.60 (dd, J=11.3, 3.2 Hz, 1H), 3.27-3.18 (m, 1H), 3.14 (dd, J=19.6, 13.0 Hz, 1H), 2.91 (t, J=10.7 Hz, 1H), 2.69-2.58 (m, 1H), 2.57-2.49 (m, 3H), 2.45-2.31 (m, 2H), 2.31-2.11 (m, 6H), 1.80 (dd, J=33.7, 17.8 Hz, 2H), 1.74-1.48 (m, 6H), 1.43-1.23 (m, 15H), 1.01-0.82 (m, 9H). HRMS (ESI) calcd for C₅₇H₇₅ClN₉O₈S₂ ⁺ [M+H]⁺: 1112.4863, found, 1112.6343.

Compound Example 144: Synthesis of (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074008)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074015) was used to prepare SIAIS074008 (white solid, 30.1 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.89 (s, 1H), 8.92 (s, 1H), 8.71 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.08 (d, J=17.2 Hz, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.74 (s, 1H), 7.51 (t, J=7.3 Hz, 1H), 7.37 (p, J=8.3 Hz, 3H), 7.29 (dd, J=11.4, 4.4 Hz, 1H), 6.70 (d, J=4.5 Hz, 1H), 6.18-6.05 (m, 1H), 5.35 (dd, J=12.6, 7.8 Hz, 1H), 4.77 (dd, J=20.6, 12.4 Hz, 2H), 4.62-4.48 (m, 3H), 4.35 (dt, J=14.9, 5.3 Hz, 1H), 4.13 (d, J=11.3 Hz, 1H), 3.98 (d, J=12.5 Hz, 1H), 3.59 (dd, J=11.3, 3.3 Hz, 1H), 3.23 (dt, J=13.7, 6.9 Hz, 1H), 3.14 (dd, J=19.2, 12.6 Hz, 1H), 3.07-2.67 (m, 5H), 2.67-2.59 (m, 1H), 2.59-2.48 (m, 3H), 2.41-2.30 (m, 2H), 2.28-2.09 (m, 5H), 2.04-1.97 (m, 1H), 1.87-1.75 (m, 2H), 1.70-1.46 (m, 5H), 1.39-1.22 (m, 14H), 0.96-0.84 (m, 6H). HRMS (ESI) calcd for C₅₈H₇₇ClN₉O₈S₂ ⁺ [M+H]⁺: 1126.5020, found, 1126.6505.

Compound Example 145: Synthesis of (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074024)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074016) was used to prepare SIAIS074024 (white solid, 31.2 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.90 (t, J=2.2 Hz, 1H), 8.35 (d, J=7.5 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J=8.0, 1.4 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.53-7.38 (m, 6H), 6.86 (d, J=1.7 Hz, 1H), 4.70 (d, J=12.8 Hz, 1H), 4.66-4.47 (m, 5H), 4.36 (d, J=15.5 Hz, 1H), 4.11 (d, J=13.5 Hz, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.80 (dd, J=10.9, 3.8 Hz, 1H), 3.36 (td, J=13.3, 6.4 Hz, 2H), 3.23 (t, J=13.1 Hz, 1H), 3.03 (t, J=11.9 Hz, 1H), 2.72 (t, J=13.2 Hz, 1H), 2.51-2.39 (m, 5H), 2.35-2.16 (m, 7H), 2.12-1.99 (m, 2H), 1.84 (d, J=12.9 Hz, 1H), 1.78 (d, J=12.8 Hz, 1H), 1.69-1.49 (m, 7H), 1.32-1.21 (m, 14H), 1.02 (s, 9H). HRMS (ESI) calcd for C₅₉H₇₉ClN₉O₈S₂ ⁺[M+H]⁺: 1140.5176, found, 1140.5167.

Compound Example 146: Synthesis of (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074025)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074019) was used to prepare SIAIS074025 (white solid, 31.5 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 7.97 (dd, J=8.0, 1.4 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.50-7.40 (m, 6H), 6.85 (s, 1H), 4.70 (d, J=13.1 Hz, 1H), 4.66-4.44 (m, 6H), 4.38-4.33 (m, 1H), 4.11 (d, J=13.6 Hz, 1H), 3.90 (d, J=11.0 Hz, 1H), 3.80 (dd, J=10.9, 3.8 Hz, 1H), 3.39-3.32 (m, 2H), 3.23 (t, J=12.3 Hz, 1H), 3.03 (t, J=11.9 Hz, 1H), 2.72 (t, J=12.3 Hz, 1H), 2.50-2.41 (m, 5H), 2.34-2.20 (m, 4H), 2.19 (s, 3H), 2.14-1.97 (m, 2H), 1.81 (dd, J=28.9, 13.0 Hz, 3H), 1.67-1.50 (m, 7H), 1.28 (dd, J=6.0, 2.0 Hz, 8H), 1.25 (d, J=6.8 Hz, 6H), 1.02 (d, J=13.8 Hz, 9H). HRMS (ESI) calcd for C₆₀H₆₁ClN₉O₈S₂ ⁺ [M+H]⁺: 1154.5333, found, 1154.2914.

Compound Example 147: Synthesis of (2S,4R)-1-((S)-2-(11-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074026)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074020) was used to prepare SIAIS074026 (white solid, 32.0 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.51-7.37 (m, 5H), 6.84 (s, 1H), 4.71 (d, J=13.0 Hz, 1H), 4.67-4.46 (m, 5H), 4.35 (dd, J=15.3, 7.4 Hz, 1H), 4.11 (d, J=13.3 Hz, 1H), 3.90 (d, J=11.1 Hz, 1H), 3.80 (dd, J=10.9, 3.9 Hz, 1H), 3.39-3.32 (m, 2H), 3.23 (t, J=12.2 Hz, 1H), 3.02 (t, J=12.0 Hz, 1H), 2.72 (t, J=12.2 Hz, 1H), 2.50-2.40 (m, 5H), 2.34-2.15 (m, 6H), 2.12-2.00 (m, 2H), 1.83 (t, J=11.2 Hz, 1H), 1.78 (d, J=13.2 Hz, 1H), 1.67-1.51 (m, 6H), 1.36 (s, 3H), 1.29 (dd, J=6.0, 2.0 Hz, 8H), 1.25 (d, J=6.8 Hz, 6H), 1.02 (d, J=13.3 Hz, 9H). HRMS (ESI) calcd for C₆₁H₆₃ClN₉O₈S₂ ⁺ [M+H]⁺: 1168.5489, found, 1168.3009.

Compound Example 148: Synthesis of 4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151049)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151001) was used to prepare SIAIS151049 (yellow solid, 21.4 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 7.84 (dd, J=10.1, 6.3 Hz, 1H), 7.55-7.49 (m, 3H), 7.48-7.43 (m, 1H), 7.35-7.26 (m, 1H), 7.12-7.05 (m, 1H), 7.05-6.99 (m, 1H), 6.90 (dd, J=12.7, 6.8 Hz, 1H), 6.36-6.28 (m, 1H), 5.02-4.97 (m, 1H), 4.65 (d, J=13.5 Hz, 1H), 4.44-4.38 (m, 1H), 4.20 (d, J=13.3 Hz, 1H), 3.91-3.77 (m, 2H), 3.75-3.68 (m, 2H), 3.51-3.45 (m, 2H), 3.29-3.21 (m, 1H), 2.86-2.77 (m, 3H), 2.74-2.60 (m, 3H), 2.12 (d, J=11.7 Hz, 2H), 2.08-2.01 (m, 1H), 1.99-1.84 (m, 5H). HRMS (ESI) calcd for C₃₉H₄₀C₁₂FN₈O₇ ⁺ [M+H]⁺: 821.2376; found, 821.2334.

Compound Example 149: Synthesis of 4-((2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl) ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151050)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151004) was used to prepare SIAIS151050 (yellow solid, 31.8 mg, 83%). ¹H NMR (500 MHz, MeOD) δ 7.88 (d, J=5.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.55-7.49 (m, 2H), 7.48-7.41 (m, 1H), 7.31-7.27 (m, 1H), 7.08 (d, J=1.7 Hz, 1H), 6.98-6.90 (m, 2H), 6.32-6.27 (m, 1H), 5.06-4.99 (m, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.44-4.36 (m, 1H), 4.15 (d, J=13.7 Hz, 1H), 3.85-3.71 (m, 2H), 3.70-3.61 (m, 6H), 3.40-3.34 (m, 2H), 3.25 (t, J=13.0 Hz, 1H), 2.90-2.66 (m, 5H), 2.60-2.52 (m, 1H), 2.14-2.05 (m, 3H), 2.01-1.83 (m, 5H). HRMS (ESI) calcd for C₄₁H₄₄C₁₂FN₈O₈ ⁺ [M+H]⁺: 865.2638; found, 865.2602.

Compound Example 150: Synthesis of 4-((2-(2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl) ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151051)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151005) was used to prepare SIAIS151051 (yellow solid, 36.7 mg, 91%). ¹H NMR (500 MHz, MeOD) δ 7.91 (d, J=1.6 Hz, 1H), 7.60 (s, 1H), 7.56-7.54 (m, 1H), 7.52-7.46 (m, 2H), 7.31-7.27 (t, J=8.6 Hz, 1H), 7.12-7.08 (m, 1H), 7.01-6.92 (m, 2H), 6.33-6.27 (m, 1H), 5.07-5.01 (m, 1H), 4.63 (d, J=11.1 Hz, 1H), 4.45-4.39 (m, 1H), 4.16 (d, J=13.5 Hz, 1H), 3.80-3.70 (m, 2H), 3.66-3.59 (m, 10H), 3.45-3.34 (m, 2H), 3.29-3.24 (m, 1H), 2.87-2.64 (m, 5H), 2.61-2.52 (m, 1H), 2.19-2.06 (m, 3H), 2.03-1.83 (m, 5H). HRMS (ESI) calcd for C₄₃H₄₈Cl₂FN₈O₉ ⁺ [M+H]⁺: 909.2900; found, 909.3068.

Compound Example 151: Synthesis of 4-((15-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151060)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151006) was used to prepare SIAIS151060 (yellow solid, 27.7 mg, 65%). ¹H NMR (500 MHz, MeOD) δ 7.92 (s, 1H), 7.59 (d, J=17.3 Hz, 2H), 7.52-7.42 (m, 2H), 7.29 (td, J=8.7, 1.8 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.02-6.98 (m, 2H), 6.33-6.29 (m, 1H), 5.03 (dd, J=12.8, 5.5 Hz, 1H), 4.62 (d, J=13.2 Hz, 1H), 4.48-4.38 (m, 1H), 4.16 (d, J=13.4 Hz, 1H), 3.77-3.73 (m, 2H), 3.69-3.66 (m, 2H), 3.63-3.59 (m, 12H), 3.45-3.38 (m, 2H), 3.29-3.25 (m, 1H), 2.89-2.80 (m, 2H), 2.78-2.68 (m, 3H), 2.64-2.59 (m, 1H), 2.17-2.07 (m, 3H), 2.03-1.86 (m, 5H). HRMS (ESI) calcd for C₄₅H₅₂C₁₂FN₈O₁₀ ⁺ [M+H]⁺: 953.3162; found, 953.4072.

Compound Example 152: Synthesis of 4-((18-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151061)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151007) was used to prepare SIAIS151061 (yellow solid, 27.0 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 7.93 (s, 1H), 7.60 (d, J=14.4 Hz, 2H), 7.53-7.47 (m, 2H), 7.29 (t, J=8.6 Hz, 1H), 7.11 (s, 1H), 7.02-6.99 (m, 2H), 6.34-6.28 (m, 1H), 5.03 (dd, J=12.8, 5.5 Hz, 1H), 4.63 (d, J=12.9 Hz, 1H), 4.48-4.38 (m, 1H), 4.15 (d, J=13.9 Hz, 1H), 3.77-3.73 (m, 2H), 3.72-3.66 (m, 2H), 3.63 (s, 3H), 3.62-3.55 (m, 13H), 3.44-3.41 (m, 2H), 3.29-3.25 (m, 1H), 2.87-2.59 (m, 6H), 2.20-2.06 (m, 3H), 2.01-1.84 (m, 5H). HRMS (ESI) calcd for C₄₇H₅₆C₁₂FN₈O₁₁ [M+H]⁺: 997.3424; found, 997.4381.

Compound Example 153: Synthesis of 4-((2-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151083)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151025) was used to prepare SIAIS151083 (yellow solid, 18.4 mg, 54%). ¹H NMR (500 MHz, MeOD) δ 7.95 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.56-7.45 (m, 2H), 7.28 (t, J=8.5 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.98 (dd, J=8.5, 2.5 Hz, 1H), 6.34 (q, J=6.6 Hz, 1H), 5.06 (dd, J=12.5, 5.4 Hz, 1H), 4.64 (d, J=13.5 Hz, 1H), 4.55-4.46 (m, 1H), 4.29-4.16 (m, 2H), 4.08 (d, J=13.3 Hz, 1H), 3.35-3.31 (m, 1H), 2.95 (t, J=12.6 Hz, 1H), 2.88-2.80 (m, 1H), 2.78-2.64 (m, 2H), 2.24-2.04 (m, 4H), 1.94 (d, J=6.6 Hz, 4H). HRMS (ESI) calcd for C₃₆H₃₄C₁₂FN₈O₆[M+H]⁺: 763.1957; found, 763.1696.

Compound Example 154: Synthesis of 4-((3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151084)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151026) was used to prepare SIAIS151084 (yellow solid, 22 mg, 64%). ¹H NMR (500 MHz, MeOD) δ 7.85 (s, 1H), 7.65-7.54 (m, 3H), 7.51 (dd, J=8.9, 4.7 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 7.16-7.11 (m, 2H), 7.05-7.01 (m, 1H), 6.35 (q, J=6.0 Hz, 1H), 5.06-4.97 (m, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.45-4.39 (m, 1H), 4.12-4.06 (m, 1H), 3.75-3.63 (m, 2H), 3.26-3.22 (m, 1H), 2.89-2.78 (m, 3H), 2.74-2.61 (m, 3H), 2.10-2.00 (m, 3H), 1.95 (d, J=6.6 Hz, 3H), 1.82-1.70 (m, 2H). HRMS (ESI) calcd for C₃₇H₃₆C₁₂FN₈O₆ [M+H]⁺: 777.2113; found, 777.1842.

Compound Example 155: Synthesis of 4-((4-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151081)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151019) was used to prepare SIAIS151081 (yellow solid, 26.3 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 7.88 (d, J=2.8 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.31-7.25 (m, 1H), 7.14 (d, J=1.3 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.02-6.94 (m, 1H), 6.34 (q, J=6.6 Hz, 1H), 5.07-4.99 (m, 1H), 4.64 (d, J=13.5 Hz, 1H), 4.48-4.38 (m, 1H), 4.08 (d, J=13.5 Hz, 1H), 3.42 (t, J=6.7 Hz, 2H), 3.25 (t, J=13.0 Hz, 1H), 2.87-2.80 (m, 2H), 2.75-2.65 (m, 2H), 2.62-2.57 (d, J=7.1 Hz, 1H), 2.56-2.50 (m, 1H), 2.16-2.04 (m, 3H), 2.03-1.96 (m, 2H), 1.95 (d, J=6.6 Hz, 3H), 1.87-1.77 (m, 2H). HRMS (ESI) calcd for C₃₈H₃₈C₁₂FN₈O₆ [M+H]⁺: 791.2270; found, 791.1991.

Compound Example 156: Synthesis of 4-((5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151082)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151020) was used to prepare SIAIS151082 (yellow solid, 25.0 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 7.91 (s, 1H), 7.64-7.62 (m, 2H), 7.59 (m, 1H), 7.55-7.49 (m, 2H), 7.28 (t, J=8.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.37-6.32 (m, 1H), 5.06-4.95 (m, 1H), 4.63 (d, J=14.0 Hz, 1H), 4.48-4.42 (m, 1H), 4.08 (d, J=13.3 Hz, 1H), 3.41-3.35 (m, 2H), 3.30-3.24 (m, 1H), 2.88-2.76 (m, 2H), 2.75-2.62 (m, 2H), 2.55-2.48 (m, 2H), 2.17-2.03 (m, 3H), 1.95 (d, J=6.6 Hz, 3H), 1.91-1.78 (m, 2H), 1.77-1.68 (m, 4H). HRMS (ESI) calcd for C₃₉H₄₀C₁₂FN₈O₆[M+H]⁺: 805.2426; found 805.2123.

Compound Example 157: Synthesis of 4-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151085)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151027) was used to prepare SIAIS151085 (yellow solid, 19.5 mg, 54%). ¹H NMR (500 MHz, MeOD) δ 7.91 (s, 1H), 7.63 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.53-7.49 (m, 2H), 7.28 (t, J=8.6 Hz, 1H), 7.16-7.11 (m, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.99 (dd, J=7.1, 1.8 Hz, 1H), 6.36-6.31 (m, 1H), 5.04-5.00 (m, 1H), 4.64 (d, J=13.5 Hz, 1H), 4.48-4.42 (m, 1H), 4.10 (d, J=13.7 Hz, 1H), 3.35 (t, J=6.8 Hz, 2H), 3.30-3.23 (m, 1H), 2.87-2.78 (m, 2H), 2.75-2.65 (m, 2H), 2.53-2.43 (m, 2H), 2.21-2.05 (m, 3H), 1.95 (d, J=6.7 Hz, 3H), 1.93-1.79 (m, 2H), 1.74-1.66 (m, 4H), 1.54-1.47 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₂C₁₂FN₈O₆[M+H]⁺: 819.2583; found 819.2583.

Compound Example 158: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide. (SIAIS220030)

Step 1: Synthesis of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl) carbamate (SIAIS220025) According to Scheme 16

SIAIS151054 (1 g, 2.85 mmol) and anhydrous tetrahydrofuran (15 mL) were added to a three-necked flask, the mixture was evacuated and replaced with nitrogen three times, then NaH (60% in oil, 342 mg, 8.55 mmol) was added in portions under ice-water bath, the resulting mixture was stirred under ice-water bath for 1 h, then methyl iodide (2 g, 8.55 mmol) was slowly added dropwise to the reaction system and the solution was stirred at room temperation for 5 h. When the reaction was complete, water was added slowly under ice-water bath to quench the reaction, the resulting solution was extracted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a yellow oil (SIAIS220025), the crude was used for the following reaction without further purification. (1000 mg, 96%)¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=9.4 Hz, 1H), 6.42 (dd, J=9.4, 2.5 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 4.38-4.20 (m, 1H), 3.98 (d, J=13.0 Hz, 2H), 3.94 (s, 3H), 3.01 (t, J=12.0 Hz, 2H), 2.72 (s, 3H), 1.80-1.72 (m, 4H), 1.47 (s, 9H). HRMS (ESI) calcd for C18H₂₅N₃O₅ ⁺ [M+H]⁺, 366.2023; found, 366.2019.

Step 2: Synthesis of tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl) carbamate (SIAIS220028) According to Scheme 16

SIAIS220025 (900 mg, 2.46 mmol), ethanol (15 mL) and water (15 mL) were added to a egg-shaped flask, followed by ammonium chloride (520 mg, 9.84 mmol) and iron powder (700 mg, 12.30 mmol), then the resulting mixture was slowly heated to reflux for 2 h. When the reaction was complete, the crude mixture was concentrated under reduced pressure, extracted with DCM (3×50 mL), the combined organic layer was washed with water and brine (20 mL), then dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford SIAIS220028 in 85% yield (700 mg) as a white solid. The crude was used for the following reaction without further purification. 1H NMR (500 MHz, CDCl₃) δ 6.63 (d, J=8.3 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 3.83 (s, 3H), 3.56-3.50 (m, 3H), 2.77 (s, 3H), 2.70 (t, J=11.5 Hz, 2H), 1.91-1.83 (m, 2H), 1.75-1.70 (m, 2H), 1.47 (s, 9H). HRMS (ESI) calcd for C₁₈H₃₀N₃O₃ ⁺[M+H]⁺, 336.2282; found, 336.2286.

Step 3: Synthesis of tert-butyl (1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)Piperidin-4-yl)(methyl) carbamate (SIAIS220029A) according to scheme 16

To a solution of 2,5-dichloro-N-(2-(dimethylphosphoryl)phenyl)pyrimidin-4-amine (405 mg, 1.28 mmol) in anhydrous DMF (10 mL) were added SIAIS220028 (410 mg, 1.22 mmol), Pd(OAc)₂ (29 mg, 0.13 mmol), Xantphos (64 mg, 0.13 mmol) and Cs₂CO₃(1.26 g, 3.84 mmol) in a 100 mL egg-shaped flask, the solution was purged and refilled with argon three times. Then the mixture was slowly heated to 110° C. and stirred for 7 h. After the starting material was consumed, the reaction mixture was filtered through a pad of silica gel, then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by silica gel chromatography (eluent: MeOH/DCM=3:97) to give the title compound (300 mg, 38%) as a brown solid. ¹H NMR (500 MHz, CDCl₃) δ 10.80 (s, 1H), 8.62 (dd, J=8.4, 4.4 Hz, 1H), 8.09 (d, J=9.5 Hz, 2H), 7.49 (t, J=7.9 Hz, 1H), 7.31-7.27 (m, 1H), 7.12 (dd, J=10.4, 4.3 Hz, 1H), 6.56 (d, J=2.1 Hz, 1H), 6.50 (dd, J=8.8, 2.3 Hz, 1H), 4.30-4.10 (m, 1H), 3.88 (d, J=8.4 Hz, 3H), 3.65 (d, J=12.2 Hz, 2H), 2.78 (s, 3H), 2.84-2.72 (m, 2H), 1.93-1.86 (m, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.79-1.73 (m, 2H), 1.48 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₁ClN₆O₄P⁺ [M+H]⁺, 615.2610; found, 615.2606.

Step 4: Synthesis of SIAIS220029B according to scheme 16

To a solution of SIAIS220029A (250 mg, 0.40 mmol) in DCM (6 mL) was added TFA (2 mL) at room temperature, the resulting solution was stirred at room temperature for 1 h. When the reaction was complete detected by LC-MS, most of the solvent was removed under the reduced pressure, 10 mL 10% MeOH/DCM was added, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, then extracted with DCM, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure to afford SIAIS220029B. The crude was used for the following reaction without further purification.

Step 5: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide (SIAIS220030) According to Scheme 16

SIAIS220029B (15 mg, 0.029 mmol, 1 equiv), SIAIS151019 (10.4 mg, 0.029 mmol, 1 equiv)), HATU (22.1 mg, 0.058 mmol, 2 equiv), DIPEA (18.7 mg, 0.145 mmol, 5 equiv) and anhydrous DMF (2 mL) were added sequentially in a 25 mL flask at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the reaction solution was purified by preparative HPLC, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220030 was obtained as yellow solid (10.2 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.34 (s, 1H), 8.06 (s, 1H), 7.69-7.60 (m, 2H), 7.56 (dt, J=8.4, 6.5 Hz, 2H), 7.31 (dd, J=15.9, 8.0 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.04 (dd, J=7.0, 4.4 Hz, 1H), 6.84-6.48 (m, 2H), 5.05 (dd, J=12.6, 5.5 Hz, 1H), 4.95 (dd, J=12.5, 5.5 Hz, 1H), 3.87 (s, 3H), 3.87-3.61 (m, 3H), 3.46-3.40 (m, 2H), 2.94 (s, 2H), 2.85-2.81 (m, 2H), 2.76-2.70 (m, 2H), 2.64-2.58 (m, 2H), 2.53 (t, J=6.9 Hz, 1H), 2.17-2.05 (m, 1H), 2.03-1.95 (m, 4H), 1.87 (d, J=2.5 Hz, 3H), 1.84 (d, J=2.5 Hz, 3H), 1.76-1.70 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺, 856.3097; found, 856.3095.

Compound Example 159: Synthesis of 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS220026)

Step 1: Synthesis of (2-((2-((4-(4-((4-aminobutyl)amino)piperidin-1-yl)-2-methoxyphenyl) amino)-5-chloropyrimidine-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS220022) according to scheme 17

SIAIS151101 (100 mg, 0.20 mmol), tert-butyl (4-bromobutyl) carbamate (76 mg, 0.30 mmol), DIPEA (129 mg, 1.00 mmol) and NMP (3 mL) were added sequentially in a 50 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 90° C. under an atmosphere of nitrogen and then stirred for 2 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220022 was obtained as a brown solid (30 mg, 22%). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J=8.0, 4.4 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.62 (dd, J=14.0, 6.4 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.27 (t, J=6.9 Hz, 1H), 6.67 (d, J=2.5 Hz, 1H), 6.45 (dd, J=8.8, 2.5 Hz, 1H), 3.85 (s, 3H), 3.75-3.72 (m, 2H), 3.22-3.11 (m, 1H), 3.05 (dd, J=17.3, 10.1 Hz, 2H), 2.99 (t, J=6.7 Hz, 2H), 2.78 (t, J=11.5 Hz, 2H), 2.20 (d, J=11.3 Hz, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.82-1.71 (m, 6H). HRMS (ESI) calcd for C₂₈H₄₀ClN₇O₂P⁺ [M+H]⁺, 572.2664; found, 572.2660.

Step 2: Synthesis of 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione (SIAIS220026) According to Scheme 17

SIAIS220022 (25 mg, 0.04 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (11 mg, 0.04 mmol), DIPEA (26 mg, 0.20 mmol) and NMP (1 mL) were added sequentially in a 25 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 110° C. under an atmosphere of nitrogen and then stirred for 1 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220026 was obtained as a yellow solid (2.3 mg, 17%). ¹H NMR (500 MHz, MeOD) δ 8.35-8.33 (m, 1H), 8.06 (s, 1H), 7.88-8.86 (m, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.66-7.63 (m, 2H), 7.57-7.45 (m, 2H), 7.28 (t, J=7.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 5.14-5.12 (m, 1H), 3.86 (s, 3H), 3.75-3.72 (m, 3H), 3.19-2.99 (m, 3H), 2.90-2.85 (m, 1H), 2.79-2.73 (m, 2H), 2.53-2.45 (m, 2H), 2.30-2.13 (m, 6H), 1.87-1.76 (m, 10H). HRMS (ESI) calcd for C₄₁H₄₈ClN₉O₆P⁺ [M+H]⁺, 828.3148; found, 828.3143.

Compound Example 160: Synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS220027)

Synthesis of Brigatinib Analogue D (SIAIS220023)

Brigatinib Analogue D was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1.

(2-((2-((4-(4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS220023), yellow solid, 30 mg, 27% yield. ¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J=8.2, 4.5 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.65-7.60 (m, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.28 (t, J=6.9 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.7, 2.4 Hz, 1H), 3.88-3.80 (m, 2H), 3.65 (s, 3H), 3.65-3.61 (m, 1H), 3.36-3.30 (m, 8H), 3.12-3.08 (m, 2H), 2.81 (t, J=11.7 Hz, 2H), 2.77-2.72 (m, 2H), 2.28 (d, J=12.4 Hz, 2H), 1.95-1.89 (m, 2H), 1.85 (s, 3H), 1.83 (s, 3H). HRMS (ESI) calcd for C₃₀H₄₃ClN₈O₂P⁺ [M+H]⁺: 613.2930, found 613.2925.

Synthesis of the title compound SIAIS220027:

According to step 2 of the preparation of Compound Example 159, Brigatinib Analogue D (SIAIS220023) instead of SIAIS220022 was used to prepare SIAIS220027 (yellow solid, 3.1 mg, 23%). ¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J=8.3, 4.5 Hz, 1H), 8.04 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.64-7.56 (m, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.27 (t, J=6.7 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.69 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.7, 2.4 Hz, 1H), 5.34 (t, J=4.8 Hz, 1H), 5.07 (dd, J=12.6, 5.6 Hz, 1H), 4.60-4.56 (m, 4H), 3.86 (s, 3H), 3.79 (d, J=12.0 Hz, 2H), 3.64 (s, 1H), 2.88-2.86 (m, 1H), 2.77-2.75 (m, 2H), 2.21-2.17 (m, 4H), 2.16-2.10 (m, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.63-1.57 (m, 2H), 1.40-1.36 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₁ClN₁₀O₆P⁺ [M+H]⁺: 869.3414, found 869.3414.

Comparative Example 161: Synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS1210003)

Step 1: Synthesis of 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (SIAIS1213161) According to Scheme 18

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (2 g, 7.24 mmol), Potassium carbonate (2 g, 14.48 mmol) and DMF (8 mL) were added sequentially in a 50 mL egg-shaped flask at RT, then methyl iodide (2 g, 14.48 mmol) was slowly added dropwise to the reaction system under an atmosphere of nitrogen and the solution was slowly heated to 60° C. and stirred for 4 h. When the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1213161 was obtained as a gray solid (736 mg, 35%). ¹H NMR (500 MHz, DMSO) δ 7.97-7.93 (m, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.74 (t, J=8.9 Hz, 1H), 5.22 (dd, J=13.1, 5.4 Hz, 1H), 3.02 (s, 3H), 2.99-2.92 (m, 1H), 2.80-2.75 (m, 1H), 2.58-2.52 (m, 1H), 2.11-2.05 (m, 1H). HRMS (ESI) calcd for C₁₄H₁₂FN₂O₄ ⁺ [M+H]⁺, 291.0776; found, 291.0771.

Step 2: Synthesis of (2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) aminoacetic acid (SIAIS1213171) According to Scheme 18

SIAIS1213161 (500 mg, 1.72 mmol), tert-butyl aminoacetate (339 mg, 2.59 mmol), DIPEA (668 mg, 5.17 mmol) and NMP (5 mL) were added sequentially in a 50 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 110° C. under an atmosphere of nitrogen and then stirred for 3 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired tert-butyl ester intermediate was obtained. This intermediate was added to a 25 mL flask, followed by DCM (5 mL) and TFA (2 mL), then stirred at room temperature for 1 h. After concentration under reduced pressure and freeze-drying, the desired product SIAIS1213171 was obtained as yellow solid (421 mg, 71% yield). ¹H NMR (500 MHz, MeOD) δ 7.58 (dd, J=8.5, 7.2 Hz, 1H), 7.11 (d, J=7.0 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 5.10 (dd, J=12.9, 5.5 Hz, 1H), 4.13 (s, 2H), 3.15 (s, 3H), 2.88 (d, J=4.0 Hz, 2H), 2.73-2.65 (m, 1H), 2.14-2.06 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M+H]⁺, 346.1034; found, 346.1030.

Step 3: Synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS1210003) According to Scheme 18

Brigatinib Analogue C SIAIS164005 (15 mg, 0.026 mmol, 1 equiv), SIAIS1213171 (9 mg, 0.026 mmol, 1 equiv)), HOAT (7.1 mg, 0.052 mmol, 2 equiv), EDCI (10 mg, 0.052 mmol, 2 equiv) DMF (2 mL) and NMM (15.2 mg, 0.15 mmol, 5 equiv) were added sequentially in a reaction bottle at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the reaction solution was purified by preparative HPLC, eluent (v/v): acetonitrile/(water+0.5% HCl)=10%-100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1210003 was obtained as yellow solid (8.8 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 8.41 (s, 1H), 8.09 (d, J=17.8 Hz, 1H), 7.69 (dd, J=14.1, 7.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.12 (d, J=7.0 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.61 (d, J=7.9 Hz, 1H), 5.11 (dd, J=12.5, 5.5 Hz, 1H), 4.28 (s, 2H), 3.99 (d, J=12.4 Hz, 2H), 3.88 (s, 3H), 3.71-3.34 (m, 9H), 3.16 (s, 3H), 2.99-2.82 (m, 3H), 2.79-2.70 (m, 2H), 2.29 (d, J=11.4 Hz, 2H), 2.19-2.08 (m, 1H), 2.03-1.94 (m, 2H), 1.89 (d, J=13.6 Hz, 6H). HRMS (ESI) calcd for C₄₄H₅₁ClN₁₀O₇P⁺ [M+H]⁺, 897.3363; found, 897.2919.

Bioactivity Assay Biological Materials

Halt proteinase and phosphatase inhibitor (Thermo Fisher)

-   -   Cell TITER BLUE detection kit (Promega)     -   Cell TITER GLO detection kit (Promega)     -   RPMI1640 and serum from (Gibico company)     -   Cell Counting Kit-8 (CCK-8, WST) reagent (Dojindo)     -   Fetal Bovine Serum (FBS) (Gibico)     -   Penicillin-Streptomycin (Gibico)     -   SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher)     -   SuperSignal West Femto Maximum Sensitivity Substrate (Thermo         Fisher)     -   Cycloheximide (Sigma)         Antibodies: antibodies of ALK (#3633S) and p-ALK (#6962S), AKT         (#4691S), p-AKT (#4060S), p-ERK (#4370) and ERK (#9107S) were         purchased from Cell Signaling Technology, Tunulin and GAPDH         antibody were purchased from Abcam.

Cell Culture

SR (NPM-ALK) and NCI-H2228 (EML4-ALK, V3) cells were purchased from ATCC. NCI-H3122 (EML4-ALK, V1) cells were from NCI (Bethesda, Md., see ref: Fujishita et al., 2003). PC9 (EGFR, exon 19 del) and PC9Brc1 (EGFR, exon 19 del+T790M) were got as previous and as a gift of Katerin Politi (Xiaoling Song et al., 2015). All Cells were cultured in RPMI1640 medium with 10% FBS and Penicillin-Streptomycin in 37° C. incubator with 5% CO₂. All cell lines were maintained in active growing state without reaching confluence, and all cell lines were STR identified and examined as mycoplasma free by regular check.

Western Blot

Cancer cells were seeded in 1 ml RPMI1640 medium in 24-well plate at the density of 3×10{circumflex over ( )}5 or 1.5×10{circumflex over ( )}5 cells/ml. The next day cells were treated with different concentration of drugs for 16 hours. Then cells were washed twice with PBS and lyzed in RIPA lysis buffer with Halt Proteinase and Phosphotase inhibitor. Equal amount of proteins were loaded to run SDS-PAGE gels after denature. The gels were blotted to PVDF membrane. After incubating with first and secondary antibodies, the images were developed using SuperSignal West Pico Chemiluminescent Substrate.

DC₅₀ (concentration required to degrade protein by half) were calculated based on the intensity from western blot, and data were analyzed via Prism GraphPad with non-linear regression.

Evaluation of compounds IC50s

Cells were seeded at specific density in 96 well plates one day before treatment. Cells were treated with a series concentration of different compounds and incubated for 72 hours. Viable cells were measured via CCK8 reagent and IC50s were calculated via Prism Graphad. Experiments were repeated at least three times.

Colony Formation Assay

Cell were digested to become single cell suspension. Cells were seeded in the intensity of 250 cells/well in 12 well plate. Treated cells at the concentration of 100, 250, 500 nM. Fixed cells 2-3 weeks after and stained cells with crystyl violate.

Results:

The PROTAD molecules developed in the present disclosure were based on ALK tyrosine kinase inhibitors, which can be chosen from Criztinib, Ceritinib, Alectinib, Brigatinib, TAE684, ASP3026, GSK1838795A, AZD3463, Entrectinib (RXDX-101) and Ensartinib (X-396) etc. Different ALK inhibitors-based ALK PROTAD molecules can inhibit ALK kinase activity, degrade ALK proteins, and the proliferation of ALK mutant positive cells. These ALK PROTAD molecules can be developed into new therapeutic ways to treat cancer patients.

I. Bioactivity Assay for Brigatinib-Based PROTAD Molecule

1. Effect of Brigatinib Based PROTAD Molecule on the Growth Inhibition on ALK Mutant Positive Cells

We performed dose-dependent effect test for these compounds in SR cells, which contain NPM-ALK gene fusion and highly sensitive to ALK inhibitors. SR cells were treated with different concentration of PROTAD molecules (started from 10 uM, 3 or 5 folds dilution for 10 concentrations) for 72 hours, CCK8 reagent were then used to examinate cell number for detection for the IC50s. Experiments were repeated for more than 3 times, results were summarized in Table 3.

Results showed that Brigatinib based on PROTAD molecules can effectively inhibit the growth of SR cells. The IC50 of Brigatinib in SR cells was 2.8 nM. The compounds we developed kept about similar growth inhibition effect as Brigatinib. Some of the compounds of the present invention had significant lower IC50 in killing SR cells. For example, the IC50 of compound SIAIS1197055 in SR cells was about 1 nM.

Besides above, we also tested the dosage-dependent effects on the growth inhibition in H2228 cells. The compounds we developed also showed growth inhibition on H2228 cells. (Table 3).

TABLE 3 The IC50 of Brigatinib-based PROTAD molecules in ALCL and lung adenocarcinoma cell lines. Test Cell line PROTAD compounds reagent IC₅₀ (nM) SR Brigatinib WST 2.8 ± 0.4 SR Brigatinib Analogue A(SIAIS1197135) WST 1.6 ± 1.0 SR SIAIS1197065 WST 20.7 ± 14.9 SR SIAIS1197067 WST 16.1 ± 6.1  SR SIAIS1197069 WST 22.3 ± 18.2 SR SIAIS1197073 WST 34.2 ± 23.9 SR SIAIS1197055 WST 1.0 ± 0.7 SR SIAIS1197057 WST 17.7 ± 9.6  SR SIAIS1197059 WST 10.7 ± 6.2  SR SIAIS1197061 WST 8.0 ± 4.4 SR SIAIS1197063 WST 14.1 ± 7.3  SR SIAIS1197077 WST 7.9 ± 4.9 SR SIAIS1197087 WST 10.6 ± 2.4  SR SIAIS197079 WST 15.9 ± 8.5  SR SIAIS1197081 WST 32.5 ± 19.8 SR SIAIS1197083 WST 49.9 ± 30.8 SR SIAIS1197085 WST 62.5 ± 39.2 SR SIAIS1197145 WST 8.5 ± 5.6 SR SIAIS1197147 WST 14.2 ± 8.2  SR SIAIS1197149 WST 8.2 ± 3.9 SR SIAIS1197151 WST 16.7 ± 7.3  SR SIAIS1197153 WST 4.6 ± 1.9 SR SIAIS1197155 WST 3.4 ± 0.5 SR SIAIS1197157 WST 3.1 ± 1.3 SR Brigatinib Analogue B(SIAIS151101) WST 1.7 ± 1.4 SR SIAIS151113 WST 7.5 ± 5.2 SR SIAIS151114 WST 10.9 ± 7.5  SR SIAIS151115 WST 8.0 ± 3.2 SR SIAIS151116 WST 15.3 ± 9.8  SR SIAIS151117 WST 30.9 ± 21.3 SR SIAIS151120 WST 11.4 ± 7.8  SR SIAIS151121 WST 20.4 ± 8.5  SR SIAIS151118 WST 0.9 ± 0.2 SR SIAIS151119 WST 1.6 ± 1.0 SR SIAIS151123 WST 1.9 ± 1.5 SR SIAIS219151 WST 102.3 ± 4.8  SR SIAIS219128 WST 6.67 ± 1   SR SIAIS219152 WST 3.78 ± 0.4  SR SIAIS219153 WST 3.12 ± 0.2  SR SIAIS219154 WST 3.8 ± 0.2 SR SIAIS219170 WST 10.8 ± 1.4  SR SIAIS220030 WST 5.8 SR SIAIS220026 WST 7.4 SR SIAIS164157 WST 15.7 ± 15.0 SR SIAIS151124 WST 76.9 ± 15.9 SR SIAIS151128 WST 6.3 ± 0.2 SR SIAIS151125 WST 61.9 ± 30.5 SR SIAIS151126 WST 31.9 ± 11.9 SR SIAIS151127 WST 36.4 ± 23.5 SR SIAIS164143 WST 11.7 ± 4.2  SR SIAIS164144 WST 13.6 ± 9.1  SR SIAIS164145 WST 10.3 ± 6.3  SR SIAIS164146 WST 3.6 ± 2.1 SR SIAIS164147 WST 2.0 ± 1.2 SR SIAIS164148 WST 1.5 ± 0.8 SR SIAIS164149 WST 2.3 ± 2.0 SR SIAIS1210117 WST 1.7 ± 1.0 SR Brigatinib Analogue C(SIAIS164005) WST 6.7 ± 3.1 SR SIAIS164007 WST 3.8 ± 1.9 SR SIAIS164008 WST 3.6 ± 2.1 SR SIAIS164009 WST 5.3 ± 1.7 SR SIAIS164016 WST 11.2 ± 6.8  SR SIAIS164017 WST 14.0 ± 8.6  SR SIAIS164018 WST 2.0 ± 1.4 SR SIAIS164019 WST 9.6 ± 8.0 SR SIAIS164020 WST 2.9 ± 1.5 SR SIAIS164021 WST 7.4 ± 5.0 SR SIAIS164022 WST 3.3 ± 2.2 SR SIAIS164023 WST 4.8 ± 2.7 SR SIAIS219073 WST 1.8 ± 1   SR SIAIS219155 WST 4.34 ± 0.4  SR SIAIS219156 WST 3.09 ± 0.2  SR SIAIS219157 WST 1.99 ± 0.2  SR SIAIS219124 WST 2.47 ± 0.6  SR SIAIS219158 WST 30.3 ± 3.8  SR SIAIS220027 WST 3.8 SR SIAIS164152 WST 7.9 ± 3.5 SR SIAIS164041 WST 42.7 ± 29.4 SR SIAIS164032 WST 54.5 ± 31.2 SR SIAIS164033 WST 50.1 ± 34.9 SR SIAIS164034 WST 88.6 ± 63.0 SR SIAIS164035 WST 41.8 ± 24.7 SR SIAIS164120 WST 19.2 ± 8.8  SR SIAIS164121 WST 21.6 ± 12.5 SR SIAIS164122 WST 12.1 ± 9.2  SR SIAIS164123 WST 11.4 ± 8.1  SR SIAIS164124 WST 9.5 ± 8.1 SR SIAIS164125 WST 9.0 ± 5.7 SR SIAIS164126 WST 8.0 ± 6.7 SR SIAIS164153 WST 55.9 ± 19.9 H2228 Brigatinib WST 45.2 H2228 SIAIS151118 WST 346.3 H2228 SIAIS1210117 WST 30.3 H2228 SIAIS164008 WST 74.0 H2228 SIAIS164018 WST 17.9 H2228 SIAIS164023 WST 15.5

1.2 Effect of Brigatinib Based ALK PROTADS on the Level of ALK Protein

The effect of Brigtinib based PROTAD molecules on the ALK protein total level were studied by western blot in ALCL SR (NPM-ALK) cell line and lung adenocarcinoma cell line H2228 and H3122 (EML4-ALK). The results were shown in FIGS. 1-6 and table 6. SR cells were treated with Brigatinib at different concentrations (0, 10, 50, 100, 500 nM) for 16 hours. Results indicated that Brigatinib did not degrade ALK proteins (FIG. 1).

The effects of Brigatinib Analogue A-based PROTAD compounds on ALK protein level were shown in FIGS. 1-2 and Table 6. With the increase of concentration, more ALK proteins were degraded in lung cancer H3122 cells. In the meanwhile, the phosphorylation of ALK protein was also significantly inhibited (FIG. 2).

Results showed Brigatinib Analogue B based PROTADs molecules not only significantly induced ALK protein degradation (FIGS. 3-4 and table 6), but also significantly reduced the phosphorylation of ALK protein (FIGS. 4-5). Besides that, the down-stream signaling pathway such as PI3K/AKT pathway was also significantly inhibited.

The results for the effect of Brigatinib Analogue C based PROTADs molecules on ALK protein degradations were shown in FIG. 6 and table 6. In SR cell line, parental drug Brigatinib Analogue C (SIAIS164005) did not degrade ALK protein even at the concentration of 500 n. However, Brigatinib Analogue C based PROTAD compounds effectively degrade ALK proteins. PROTAD compound SIAIS164018 degraded ALK proteins at the concentration less than 1 nM in SR cells, and a similar effects was observed in H3122 cells (FIG. 7 and table 6). Other compounds also showed the abilities to degrade ALK protein at the concentration lower than 10 nM. For example, compound SIAIS164009, SIAIS164021 and SIAIS164153 degraded ALK proteins at the concentration of 1 nM. These results indicated that the PROTADs molecules we developed had good protein degradation capabilities. Besides that, the compounds we developed also significantly inhibited the phosphorylation of ALK protein (FIG. 7).

The effects of compounds SIAIS164008 and SIAIS164018 of the present invention on the activation of ALK mediated signaling pathways were also studied in SR cells and H2228 cells. Both of these two compounds effectively degrade ALK proteins at nano mole concentration. In the meanwhile, both compounds inhibited the phophorylation of ALK proteins at the concentration of 0.1 nM and downstream signaling pathway such as PI3K/AKT, MEK/ERK and STAT3 pathway were all significantly inhibited. Both SIAIS164008 and SIAIS164018 also inhibited the phosphorylation of ALK protein and activation of PI3K/AKT pathway as well in lung cancer cell line H2228 cells although H2228 cells were less sensitive than SR cells. The overall effect of compound of SIAIS164018 was better than that of SIAIS164008.

In summary, we successfully developed Brigatinib based PROTAD compounds. These PROTAD compounds reduced ALK protein levels, blocked ALK down-stream signaling, inhibited the growth of cancer cells, and potentially could be used in cancer therapy.

II. Bioactivity Assay for Alectinib Based ALK PROTAD

Alectinib (Roche) was approve on Nov. 7, 2017 by FDA to treat ALK mutant positive metastic non-small cell lung cancer. Three different Alectinib derivatives were designed and generated, and these three different forms of Alectinib derivatives were used to develop ALK PROTADs compounds. The IC50s of these Alectinib based ALK PROTADs compounds were tested in SR cells and the results were listed in table 4. The IC50 of Alectinib in SR cells was 10.6 nM. Within these different Alectinib Analogue forms, the growth inhibition effect of Alectinib Analogue A is better than that of Alectinib, while the effect of Alectinib Analogue B and C were slightly weaker than that of Alectinib in inhibiting the growth of SR cells. Even with the addition of different E3 linkers, the developed ALK PROTAD compounds retained the growth inhibition in SR cells.

TABLE 4 The IC50s of Alectinib based ALK PROTAD compopunds Testing Cell line Compounds name reagents IC₅₀ (nM) SR Alectinib WST 10.6 SR Alectinib Analogue A WST 2.4 SR SIAIS164012 WST 48.9 SR SIAIS164014 WST 81.0 SR SIAIS164028 WST 19.7 SR SIAIS164024 WST 35.8 SR SIAIS164026 WST 147.9 SR SIAIS164036 WST 131.9 SR SIAIS164094 WST 124.0 SR SIAIS164095 WST 71.3 SR SIAIS164096 WST 79.5 SR SIAIS164155 WST 103.7 SR SIAIS164029 WST 27.3 SR SIAIS164037 WST 152.8 SR Alectinib Analogue B(SIAIS184193) WST 14.7 SR SIAIS219023 WST 29.3 SR SIAIS219024 WST 73.1 SR SIAIS219001 WST 21.3 SR SIAIS219010 WST 31.1 SR SIAIS219011 WST 49.9 SR SIAIS219020 WST 30.3 SR SIAIS219021 WST 115 SR Alectinib Analogue C(SIAIS184192) WST 19.1 SR SIAIS219018 WST 13.3 SR SIAIS219019 WST 38.3 SR SIAIS184194 WST 24.2 SR SIAIS219003 WST 21.8 SR SIAIS219004 WST 36.8 SR SIAIS219015 WST 110.3 SR SIAIS219016 WST 80.8

The effect of Alectinib-based ALK PROTAD compounds on ALK protein level and down-stream signaling pathway were studied in ALCL cell line SR and non-small cell lung cancer cell line H3122 (FIGS. 9 and 10). Alectinib did not degrade ALK proteins at the concentration of 1-500 nM in SR cell. However, Alectinib Analogue A-based ALK PROTAD compounds could degraded ALK proteins in these cells (FIG. 9 and table 6). In addition, Alectinib based ALK PROTAD compounds also could degrade ALK protein in H3122 lung cancer cells.

The phosphorylation of ALK protein is an indication of ALK activation. ALK phosphorylation were also studied after treated ALK mutant cells with Alectinib based compounds. In H3122 cell line, Alectinib inhibited the phosphorylation of ALK but not affected the total protein level of ALK (FIG. 10). In contrast, Alectinib based ALK PROTAD compounds exhibited different degradation capabilities of ALK protein (FIG. 10 and Table 6). These ALK PROTAD compounds also inhibited the phosphorylation of ALK signaling. These results indicated that Alectinib based-ALK PROTAD compounds not only retained the capabilities to inhibit ALK phosphorylation but also able to degraded ALK proteins, which fully showed the advantage of ALK PROTAD compounds comparing to ALK kinase inhibitors.

Accordingly, Alectinib based ALK PROTAD compounds also blocked the activation of ALK downstream signaling. Parental compound Alectinib did not affect much the phosphorylation of AKT protein and some at the ERK phosphorylation. Alectinib based ALK PROTAD compounds such as SIAIS164024 and SIAIS164026 not only reduced the protein level of ALK protein, but also inhibited the phosphorylation of AKT and ERK.

In summary, Alectinib based ALK PROTAD compounds not only effectively reduced ALK protein level, but also reduced the phosphorylation of AKT and ERK.

III. Bioactivities Assay of Ceritinib and Crizotinib Based ALK PROTAD Compounds

Our data indicated that Certinib-based ALK PROTAD compounds also not only degraded ALK protein, inhibited ALK kinase activities, but also inhibited the growth of ALK mutant positive cells. In the meanwhile, Crizotinib based ALK PROTAD compounds also could reduced the level of ALK protein.

3.1 Both Ceritinib and Criztinib-Based ALK PROTAD Compounds Effectively Reduced ALK Protein Level

Ceritnib did not affect ALK protein level in H3122 cells even at the concentration as high as 500 nM (FIG. 11). However, Ceritinib based-ALK PROTAD compounds could induced significant reduction of ALK protein level in the dose-dependent manner (FIG. 11 and Table 6). For example, ALK PROTAD compound SIAIS074024 reduced ALK protein level at the concentration as low as 50 nM.

Similarly, Crizotinib-based ALK PROTAD compound SIAIS151082 could also reduced ALK protein level at the concentration of about 50 nM.

3.2 the Effect on Cell Growth for Certinib-Based ALK PROTAD Compounds

The effect of Certinib-based ALK PROTAD compounds on ALK mutant positive cells were examined in H3122 cells and the results were summarized in Table 5. Certain ALK PROTAD compounds such as SIAIS074008 and SIAIS074032 had a very potent growth inhibition effect (IC50 at the nano mole range) in SR and H3122 cells (Table 5).

TABLE 5 The IC50s for Ceritinib based ALK PROTAD compounds Testing Cell line Compound name reagents IC₅₀ (μM) SR Ceritinib WST 0.016 SR SIAIS151031 WST 0.085 SR SIAIS151028 WST 0.038 SR SIAIS074017 WST 0.116 H3122 Ceritinib CTB 0.014 H3122 SIAIS074017 CTB 0.045 H3122 SIAIS074018 CTB 0.209 H3122 SIAIS074021 CTB 0.125 H3122 SIAIS074022 CTB 0.269 H3122 SIAIS074008 CTB 0.428 H3122 SIAIS074024 CTB 0.721 H3122 SIAIS074025 CTB 1.241 H3122 SIAIS074026 CTB 2.560 H3122 SIAIS074036 CTB 3.900 H3122 SIAIS151023 CTB 0.015 H3122 SIAIS151028 CTB 0.006 H3122 SIAIS151029 CTB 0.023 H3122 SIAIS151031 CTB 0.007 H3122 SIAIS151034 CTB 0.014 H3122 SIAIS151035 CTB 0.033 H3122 SIAIS151036 CTB 0.031 H3122 SIAIS151037 CTB 0.151 H3122 SIAIS151038 CTB 0.393 H3122 SIAIS151039 CTB 0.441 H3122 SIAIS151040 CTB 0.141 H3122 SIAIS151041 CTB 0.332 H3122 SIAIS151042 CTB 0.153 H3122 SIAIS151043 CTB 0.156 H3122 Ceritinib CTG 0.044 H3122 SIAIS074017 CTG 0.041 H3122 SIAIS151023 CTG 0.076 H3122 SIAIS151028 CTG 0.080 H3122 SIAIS151029 CTG 0.095 H3122 SIAIS151031 CTG 0.081 H3122 DMSO CTB 17.19 CTB: Cell Titer Blue; CTG: Cell Titer Glo.

Summary from above, the bioactivities of different ALK PROTAD compounds were evaluated in ALCL SR cell lines and non-small cell line H3122 cells. Resulted showed these ALK PROTAD compounds could effective reduced ALK protein level in SR and H3122 cell lines (Table 6). These compounds could inhibited ALK kinase activities, blocked ALK-dependent downstream signaling pathway, and finally inhibited the growth of ALK mutant positive cells.

TABLE 6 The DC50s of ALK PROTAD compounds in SR and H3122 cells ALK PROTAD Compounds DC₅₀ (nM) in SR DC₅₀ (nM)) in H3122 Brigtinib not degrade nt Brigatinib Analogue A not degrade nt SIAIS1197053 SIAIS1197065 nt 100-500 SIAIS1197067 nt 100-500 SIAIS1197069 nt 100-500 SIAIS1197073 nt 100-500 SIAIS1197055  1-10  1-50 SIAIS1197057 nt  50-500 SIAIS1197059 nt  1-50 SIAIS1197061 nt  50-500 SIAIS1197063 nt  50-500 SIAIS1197077 0.1-0.5  50-500 SIAIS164156 nt  50-500 SIAIS1197087 nt  50-500 SIAIS197079 nt  50-500 SIAIS1197081 nt  50-500 SIAIS1197083 nt  50-500 SIAIS1197085 nt  20-100 SIAIS1197145 nt  1-50 SIAIS1197147 nt  20-100 SIAIS1197149 nt  20-100 SIAIS1197151 nt  20-100 SIAIS1197153  1-50  1-50 SIAIS1197155  1-10  1-50 SIAIS1197157  1-10  1-50 Brigatinib Analogue B Not degrade Not degrade SIAIS151101 SIAIS151113 nt 100-500 SIAIS151114 nt 100-500 SIAIS151115 nt 100-500 SIAIS151116 nt 100-500 SIAIS151120 nt  20-100 SIAIS151121 nt 100-500 SIAIS151118  1-10  1-50 SIAIS151119 nt 100-500 SIAIS151123 0.1-2    1-50 SIAIS164157 nt  1-50 SIAIS151124 nt 100-500 SIAIS151128 nt 100-500 SIAIS151125 nt 100-500 SIAIS151126 nt 100-500 SIAIS151127 nt  20-100 SIAIS164143  1-10  50-100 SIAIS164144  1-10  20-100 SIAIS164145  1-10  50-100 SIAIS164146  1-10 0.1-10  SIAIS164147  1-10 0.02-1   SIAIS164148  1-10  1-50 SIAIS164149  1-10 0.02-20   SIAIS1210117 0.5-10  nt Brigatinib Analogue C Not degrade Not degrade SIAIS164005 SIAIS164007  1-10 10-50 SIAIS164008  1-10 10-50 SIAIS164009  1-10  1-10 SIAIS164016  1-10  1-10 SIAIS164017 100-500 0.02-20   SIAIS164018 0.5-1    1-10 SIAIS164019  1-10 10-20 SIAIS164020 0.5-10   1-50 SIAIS164021 0.1-0.5  1-10 SIAIS164022  1-10  1-10 SIAIS164023 0.5-10   1-10 SIAIS164152 0.5-10  10-50 SIAIS164041 10-50  10-500 SIAIS164032 100-500  20-100 SIAIS164033 100-500 100-500 SIAIS164034 100-500 100-500 SIAIS164035 100-500 100-500 SIAIS164120  1-10  10-100 SIAIS164121  1-10  50-100 SIAIS164122  1-50  50-100 SIAIS164123  1-50 10-50 SIAIS164124  1-10 100-500 SIAIS164125  1-10 10-50 SIAIS164126  1-10 10-50 SIAIS164153 100-500  1-10 Alectinib Not degrade >500 Alectinib Analogue A nt nt SIAIS164011 nt nt SIAIS164012  1-50  1-50 SIAIS164014 nt 100-500 SIAIS164028  1-50  1-10 SIAIS164029 nt nt SIAIS164024 nt  1-10 SIAIS164026 nt  1-10 SIAIS164036 nt  20-100 SIAIS164094 nt  20-100 SIAIS164095 nt nt SIAIS164096 nt nt SIAIS164155 nt 10-50 Ceritnib nt Not degrade SIAIS074017 nt 100-500 SIAIS074018 nt 100-500 SIAIS074021 nt  50-100 SIAIS074022 nt  20-100 SIAIS074024 nt 10-50 SIAIS074025 nt 100-500 SIAIS151023 nt  10-100 SIAIS151029 nt 10-50 SIAIS151037 nt  50-100 SIAIS151035 nt  50-100 SIAIS151031 nt 100-500 SIAIS151028 nt  20-100 SIAIS151032 nt  20-100 Crizotinib nt 100-500 SIAIS151060 nt 100-500 SIAIS151082 nt  1-10 SIAIS151083 nt 10-50 nt: not tested

IV. The Effect of ALK PROTAD Compounds on ALK Resistance Mutation

Drug resistance always occurs after treating ALK mutant positive lung cancer patients with ALK inhibitor drugs. The resistance mechanisms include acquiring resistance mutations in ALK protein such as gate keeper mutation L1196M and C1156Y. We tested the growth inhibition effect with Brigatinib-based ALK PROTAD compounds developed in this project in mutant ALK expressing Ba/F3 cells, and the results were summarized in table 7. Results showed that ALK PROTAD compounds not only inhibited the growth of EML4-ALK that was wild type in the ALK kinase domain, but also inhibited the growth of EML4-ALK that harbored L1196M and C1156Y mutant mutations in the kinase domain.

TABLE 7 The IC50s of Brigatinib based ALK PROTAD compounds against ALK resistant mutations IC₅₀ Cell line Compounds (nM) Ba/F3 (EML4-ALK/WT) Crizotinib 188.6 Brigatinib 11 SIAIS164008 114.6 SIAIS164018 30.9 SIAIS164023 33.6 SIAIS164142 64.7 SIAIS1210117 123.4 SIAIS151118 92 Ba/F3 (EML4-ALK/L1196M) Crizotinib 395 Brigatinib 35.9 SIAIS164008 376.2 SIAIS164018 57.4 SIAIS164023 75.8 SIAIS164142 117 SIAIS1210117 170.4 SIAIS151118 145.8 Ba/F3 (EML4-ALK/C1156Y) Crizotinib 366.8 Brigatinib 36.8 SIAIS164008 242.5 SIAIS164018 42.7 SIAIS164023 47.5 SIAIS164142 92.1 SIAIS1210117 119.5 SIAIS151118 128.9

V. The Mechanisms Study for ALK PROTAD Compounds in Cells

5.1 ALK PROTAD Compounds Reduced the Stability of ALK Proteins

The mechanism of PROTAD compound to degrade its target protein acts through recruiting E3 ubiquitining ligase to the proximity of its target protein, which leads to the target protein being highly ubiquitinzed and eventually being degraded. In order to see the mechanism of ALK PROTAD compounds we developed, we firstly examined the half-life of ALK protein. Because the total level of ALK protein was determined by both the translational activity and protein degradation, we used cyclohexmide to stop protein translation to examine the effect of ALK PROTAD compounds on ALK protein stabilities.

We listed data for Ceritinib-based ALK PROTAD compounds here as an example, and data for other ALK PROTAD compounds were tested in the same way and similar results were found. H3122 cells were firstly treated with 0.5 uM Ceritinib and Certinib based ALK PROTAD compounds for 24 hours, and 1 ug/ml cyhexmide was used to stop protein translation. The difference at the total ALK protein level will reflect the different influence of drugs on protein stability. Results showed ALK protein level did not show much difference 12 hours after Ceritinib treatment (FIGS. 11 & 13). However, ALK PROTAD compound SIAIS074017 significantly reduced ALK protein level even after 7 hours-treatment. This indicated that the ALK PROTAD compounds treatment promoted the degradation of ALK protein.

5.2 ALK PROTAD Compounds Act Through the Proteosome to have their Function

In order to study the time- and dose-dependent effect of ALK PROTAD compounds to ALK proteins, we firstly examined the effect of Brigatinib on ALK protein level (FIG. 14). ALCL cell line SR was treated with Brigatinib at a serial concentration of Brigatinib from 30 nM to 300 uM for 4-24 hours. Western blot was used to examine the level of ALK protein. Results showed with different concentration of Brigatinib even high as 300 μM did not affect ALK protein levels. And with increase of the treatment time from 4 to 24 hours, Brigatinib did not affect ALK protein levels.

We also tested the effects of an ALK PROTAD compound SIAIS1210117 on ALK protein levels within a time course. Results showed at the concentration of 100 nM, treating SR cells with SIAIS1210117 for 4 hours could lead to significant ALK protein degradation (FIG. 15). To further confirm the degradation act through E3 ubiqutinase, an inactive epimer of SIAIS1210117 were synthesized. This epimer, SIAIS219050, was similar to SIAIS1210117 in the structure except it lost the ability of recruiting E3-ligase. Results showed that this epimer did not induce degradation of ALK protein even after 24 hours treatment.

To further validate the degradation effect act through proteosome mediated pathway, we also treated cells with two different proteosome inhibitors MG132 and MLN4924 to block protein degradation (FIG. 16). Results showed that although SIAIS1210117 reduced ALK protein level in SR cells, and this effect was able to be blocked by proteosome inhibitor MG132 and MLN4924. Where as the control epimer SIAIS219050 did not have such effect. The same results were observed for ALK PROTAD compound SIAIS164018. The degradation of ALK protein by SIAIS164018 was able to be blocked by MK132 and MLN4924, and there was no such effect on the negative epimer SIAIS1210003 of SIAIS164018.

VI. The Effect of ALK PROTAD Compounds on the Colony Formation Ability of Cancer Cells

In order to see the effect of ALK PROTAD compounds on the colony formation ability of cancer cells, EML4-ALK mutant lung cancer cells H2228 were firstly seeded in 12 well plate at the density of 200 cells per well. Cells were treated with different ALK PROTAD compounds at different concentration for about 2 weeks. ALK PROTAD compounds SIAIS1210117, SIAIS164018 and their epimers were used as an example, and results were shown in FIG. 17. Both negative control epimers could not inhibit the colony formation of H2228 cells, and two ALK PROTAD compounds SIAIS1210117 and SIAIS164018 dramatically inhibited the colony formation of H2228 cells.

VII. The Effect of ALK PROTAD Compounds on EGFR Mutant Cells

7.1 ALK PROTAD Compounds Inhibited the Growth of EGFR Mutant Cells

Previous results showed that Brigatinib could inhibit the activity of EGFR. So we tested the effect of ALK PROTAD compounds on two different EGFR mutant lung cancer cell lines. PC9 cells contain EGFR exon19 deletion mutation and PC9Brc1 harbor exon 19 deletion and T790M point mutation. Results showed ALK PROTAD compounds also could inhibited the growth of EGFR mutant non-small cell lung cancer cells even for PC9Brc1 cells that carry with resistant mutations against EGFR TKIs (Tables 8-9).

TABLE 8 The IC50s of ALK PROTAD compounds in lung adenocarcinoma PC9 cells Half Inhibitory Concentration (IC₅₀) (n ≥ 3) Mean (nM) Standard Error Testing Reagent Brigatinib 102 33 CTB SIAIS164007 358 35 CTB SIAIS164008 265 28 CTB SIAIS164018 150 36 CTB SIAIS164021 434 178 CTB SIAIS164022 233 91 CTB SIAIS164023 379 92 CTB SIAIS164147 321 74 CTB SIAIS164148 153 44 CTB SIAIS164149 187 26 CTB SIAIS1210117 106 26 CTB

TABLE 9 The IC50s of ALK PROTAD compounds in lung cancer cell line PC9Brc1 Half Inhibitory Concentration (IC₅₀) Standard Error (n ≥ 3) Mean (nM) (SE) Testing Reagent Brigatinib 246 31 CTB SIAIS164007 1606 194 CTB SIAIS164008 1834 430 CTB SIAIS164018 900 166 CTB SIAIS164021 2445 1062 CTB SIAIS164022 696 428 CTB SIAIS164023 870 289 CTB SIAIS164147 1285 158 CTB SIAIS164148 1340 139 CTB SIAIS164149 988 116 CTB SIAIS1210117 460 66 CTB

7.2. The Effect of ALK PROTAD Compounds on the Colny Formation of EGFR Mutant Cells

ALK PROTOAD compounds we developed also could significantly inhibited the colony formation ability of EGFR mutant non-small cell lung cancer. Results were shown in FIG. 18 and FIG. 19. ALK PROTAD compound SIAIS1210117 and its negative control epimer SIAIS219050 were used. ALK PROTAD compound was able to inhibit the colony formation of PC9 and PC9 Brc1 cells, but its negative epimer could not.

7.3. The Growth Inhibition Effect of ALK PROTAD Compounds on EGFR Mutant Colorectal Cancer Cell Line SW48

Colorectal cancer cell line SW48 harbors an EGFR G719S mutation. We tested ALK PROTAD compounds we developed in this cell line, and we found our ALK PROTAD compounds had better growth inhibition effect than Brigatinib (see Table 10 and FIG. 20).

TABLE 10 The IC50s of ALK PROTAD compounds in SW48 cell line Half Inhibitory Concentration (IC₅₀) Mean Standard Error (n = 2) (μM) (SE) Reagent Crizotinib 0.19 0.03 CTG Alectinib 0.80 0.22 CTG Brigatinib 2.72 0.70 CTG SIAIS164008 15.25 1.68 CTG SIAIS164018 2.76 0.12 CTG SIAIS219073 >20 Na CTG SIAIS1210117 1.36 0.01 CTG SIAIS151118 1.92 0.07 CTG Na: not available

VIII. The Effect of ALK PROTAD Compounds on ROS1 Mutant Cells

Human glioblastoma cell line U118MG carries a FIG-ROS1 gene fusion. We have treated U118MG cells with ALK PROTAD compounds at a serial concentration for 72 hours and the IC50s were summarized in Table 11. Results showed that different ALK inhibitor drugs had different cell killing potency in this ROS1 mutant cell line, and ALK PROTAD compounds showed better activity than their parental compound Brigatinib in the ability to inhibit cell growth. The IC50 for Brigatinib in U118MG cells was about 6.8 μM, and Brigatinib based ALK PROTAD compound SIAIS164008 had the IC50 about 3.52M and SIAIS1210117 had an IC50 about 0.92 M (Table 11).

TABLE 11 The IC50s of ALK PROTAD compounds in glioblastoma cell line U118MG Half Inhibitory Concentration (IC₅₀) Mean Standard (n = 2) (μM) Error (SE) Reagent Crizotinib 2.57 0.39 CTG Alectinib 1.48 0.29 CTG Brigatinib 6.80 2.00 CTG SIAIS164008 3.52 3.17 CTG SIAIS164018 16.88 14.38 CTG SIAIS219073 >20 na CTG SIAIS1210117 0.92 0.09 CTG SIAIS151118 4.26 0.25 CTG na: not available

VIIII. The Effect of ALK PROTAD Compounds on FLT3 Mutant Cancer Cells

We also tested the effect of ALK PROTAD compounds we developed in FLT3 mutant cell line. MOLM13 is an acute monocytic leukemia cell line with mutation of FLT3-ITD mutation. Parental drug Brigatinib inhibited MOLM13 cells with an IC50 about 152 nM (Table 12). Selected ALK PROTAD compound SIAIS164018 and SIAIS151118 both showed a better growth inhibition effect than Brigatinib with an IC50 value of 79 nM and 101 nM respectively.

TABLE 12 The IC50s of ALK PROTAD compoundS in AML cell line MOLM13 Half Inhibitory Concentration (IC₅₀) Mean Standard Error (n = 2) (μM) (SE) Reagent Crizotinib 291 69 CTG Alectinib 255 35 CTG Brigatinib 152 14 CTG SIAIS164008 392 10 CTG SIAIS164018 79 18 CTG SIAIS219073 373 68 CTG SIAIS1210117 345 10 CTG SIAIS151118 101 9 CTG

X. The Pharmacokinetics (PK) Study of ALK PROTAD Compounds

SD rat were used to study the PK of ALK PROTAD compounds. ALK PROTAD compounds SIAIS164008, SIAIS164018, SIAIS164023 and SIAIS151118 were administrated into SD rat via three different routes: IV (Intravenous Injection), IP (Intraperitoneal Injection) and PO (paricalcitol to oral). Blood samples at different sampling time points up to 24 hours post dosing were collected from each animal and analyzed with LC-MS/MS to calculate the PK for each chemical.

Results showed that, after single dose of SD rats with 2 mg/kg ALK PROTAD compounds (SIAIS164008, SIAIS164018, SIAIS164023 and SIAIS151118) via IV, testing drugs were quickly distributed in blood, with the maximal peak levels were reached about at 0.083-2 hours, and serum clearance half-life was about 0.85, 4.65, 7.71 and 4.73 hours, and the mean value of clearance rates were about 414.27, 22.63, 88.16 and 6.35 mL/min/kg. When administrated ALK PROTAD compounds via IP at the dose of 2 mg/kg, the time to maximal serum peak level (Tmax) were about 0.42, 2.67, 2.00 and 1.67 hours for these compounds respectively, and the serum half-life were 1.54, 3.65, 1.62 and 3.27 hours respectively, and the bioavailability were 92.96%, 157.49%, 122.13%

224.67% respectively. When administrated these ALK PROTAD compounds via PO at the dose of 10 mg/kg, the Tmax were 2.75, 2.00, 3.33 and 3.33 hours respectively, and the serum half-life were 3.98, 7.09, 2.13 and 4.66 hours, and the bioavailable were 14.89%, 18.38%, 34.43% and 35.99% respectively.

In summary, ALK PROTAD compounds we developed could promote degradation of ALK protein, inhibit ALK kinase activity in, block ALK-mediated signaling pathway, and inhibit cell growth and reduce the colony formation abilities in ALK mutant positive cancer cells. In the meanwhile, developed ALK PROTAD compounds also could inhibited the growth of cancer cells harboring EGFR activating mutations, FLT3 activating mutation and ROS1 gene rearrangement with a lower IC50 value comparing to parental drug. These developed ALK PROTAD compounds also had a good PK in rat. These compounds had serum long half-life, good oral bioavailabilities, and are suitable for therapeutic treatment of human cancer.

The basic principles, main features and advantages of the present disclosure are shown and described above. Those skilled in the art should understand that the present disclosure is not limited by the foregoing embodiments, and they can make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure. These changes, substitutions and alterations fall within the scope of the present disclosure. The claimed scope of the present disclosure is defined by the appended claims and their equivalents.

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1. A compound of formula (I)

or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, in which: ALK-TKI is covalently connected to LIN via group A, and ULM is covalently connected to LIN; wherein ALK-TKI is an ALK tyrosine kinase inhibitor or an analogue thereof with the same function; LIN is a linking group, which represents a linear or branched alkylene chain, a spiro-cycloalkylene, a 1,4-piperazinylene, or a 1,3-dialkynylene group, wherein the linear or branched alkylene chain is optionally interrupted one or more times by one or more selected from the group consisting of O, C(O)NH, NHC(O), NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene group, or any combination thereof, wherein the linear or branched alkylene chain is optionally substituted with one or more substituents; ULM is a small molecule ligand of VHL or CRBN protease with ubiquitination function; and the group A is C(O) or absent.
 2. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the ALK-TKI is the structure represented by the following general formula:

wherein, R represents an alkyl group or H.
 3. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 2, wherein R represents a linear or branched C₁₋₁₀ alkyl group.
 4. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the ULM represents the structure of the following formula (II):

wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group or is absent.
 5. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the ULM represents the structure of the following formula (III):

wherein Z represents a carbonyl group or is absent.
 6. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the LIN represents: linear or branched C₁₋₂₀ alkylene chain; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)—; —(CR₁R₂)_(n1)—(O(CR₁R₂)_(n2))_(m1)—O—(CR₁R₂)_(n3)—; —(CH₂)_(n1)—(C(O)NH—(CH₂)_(n2))_(m1)—; —(CH₂)_(n1)—(C(O)NH—(CH₂)_(n2))_(m1)—(CH₂)_(n3)—; —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)—C(O)NH—(CH₂)_(n4)—(O(CH₂)_(n5))_(m2)—O—(CH₂)_(n6)—; —(CR₁R₂)_(n1)—(O(CR₁R₂)_(n2))_(m1)—O—(CR₁R₂)_(n3)—C(O)NΠ-(CR₁R₂)_(n4)—(O(CR₁R₂)_(n5))_(m2)—O—(CR₁R₂)_(n6)—; —(CH₂)_(n1)—C(O)NΠ-(O(CR₁R₂)_(n2))_(m1)—; linear or branched alkylene chain interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NΠ, S, sulfinyl, sulfonyl, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof; or —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)— in which carbon chain is interrupted one or more times by one or more selected from the group consisting of arylene, heterocyclylene, heteroarylene or any combination thereof; wherein R₁ and R₂ each independently represent a linear or branched C₁₋₁₀ alkyl group or a cycloalkyl group; and n1, n2, n3, n4, n5, n6, ml, and m2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 7. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents: —(CH₂)₂O(CH₂)₂OCH₂—; —CH₂O(CH₂)₂OCH₂—; —(CH₂)₃O(CH₂)₂—; —(CH₂)₃O(CH₂)₂O(CH₂)₂—; —(CH₂)₃O(CH₂)₃—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃—; —(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; —(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂—; or —(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃—.
 8. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents: —CH₂—; —(CH₂)₂—; —(CH₂)₃—; —(CH₂)₄—; —(CH₂)₅—; —(CH₂)₆—; —(CH₂)₇—; —(CH₂)₈—; —(CH₂)₉—; —(CH₂)₁₀—; —(CH₂)₁₁—; —(CH₂)₁₂—; —(CH₂)₁₃; —(CH₂)₁₄—; —(CH₂)₁₅—; —(CH₂)₁₆—; —(CH₂)₁₇—; —(CH₂)₁₈—; —(CH₂)₁₉—; or —(CH₂)₂₀—.
 9. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the substituent for the linear or branched alkylene chain is selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof.
 10. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 9, wherein the LIN represents a linear or branched C₁₋₂₀alkylene chain substituted with one or more substituent groups selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof.
 11. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 9, wherein the LIN represents —(CH₂)₃CH(OH)CH(OH)(CH₂)₄—.
 12. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the LIN represents: —(CH₂)_(n1)-triazolylene-(CH₂)_(n2)—, —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)-triazolylene-(CH₂)_(n4)—(O(CH₂)_(n5))_(m2)—O—(CH₂)_(n6)—, —(CH₂)_(n1)-triazolylene-(CH₂)_(n2)—(O(CH₂)_(n3))_(m1)—O—(CH₂)_(n4)—, or —(CH₂)_(n1)—(O(CH₂)_(n2))_(m1)—O—(CH₂)_(n3)-triazolylene-(CH₂)_(n4)—; and n1, n2, n3, n4, n5, n6, ml, and m2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 13. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 12, wherein the LIN represents:


14. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents: —(CH₂)₂C(O)NΠ(CH₂)₂—; —(CH₂)₃C(O)NΠ(CH₂)₃—; —(CH₂)₃C(O)NΠ(CH₂)₄—; —(CH₂)₆C(O)NΠ(CH₂)₇—; or —(CH₂)₈C(O)NΠ(CH₂)₈—.
 15. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—NHC(O)—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 16. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 15, wherein the LIN is —(CH₂)₃NHC(O)(CH₂)₃—.
 17. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—NHC(O)NΠ—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 18. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 17, wherein the LIN is —(CH₂)₄NHC(O)NΠ(CH₂)₄—.
 19. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—S—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 20. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 19, wherein the LIN is —(CH₂)₅S(CH₂)₅— or —(CH₂)₆S(CH₂)₅—.
 21. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—S(O)—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 22. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 21, wherein the LIN is —(CH₂)₅S(O)(CH₂)₅— or —(CH₂)₆S(O)(CH₂)₅—.
 23. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—S(O)₂—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 24. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 23, wherein the LIN is —(CH₂)₅S(O)₂(CH₂)₅— or —(CH₂)₆S(O)₂(CH₂)₅—.
 25. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—CH═CH—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 26. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 25, wherein the LIN is —(CH₂)₄CH═CH(CH₂)₃—.
 27. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is —(CH₂)_(n1)—C≡C—(CH₂)_(n2)— or —(CH₂)_(n1)—C≡C—C≡C—(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 28. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 27, wherein the LIN is —(CH₂)₂C═C(CH₂)₂— or —(CH₂)₅C═C(CH₂)₄—.
 29. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is a linear or branched alkylene chain interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NΠ, S, sulfinyl, sulfonyl, alkynylene, alkenylene, spiro-cycloalkylene, arylene, heterocyclylene, heteroarylene group, or any combination thereof.
 30. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 29, wherein the LIN is —(CH₂)_(n1)-piperazinylene-(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 31. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 30, wherein the LIN is: —CH₂-piperazinylene-CH₂—, —(CH₂)₂-piperazinylene-(CH₂)₂—, —(CH₂)₃-piperazinylene-(CH₂)₃—, —(CH₂)₂-piperazinylene-(CH₂)₃—, —CH₂— piperazinylene-(CH₂)₂—, —CH₂-piperazinylene-(CH₂)₃—, or —(CH₂)₂-piperazinylene-(CH₂)₃—.
 32. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 29, wherein the LIN is —(CH₂)_(n1)-phenylene-(CH₂)_(n2)—, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 33. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 32, wherein the LIN is:—CH₂-phenylene-CH₂-, —(CH₂)₂-phenylene-(CH₂)₂—, —CH₂-phenylene-(CH₂)₂—, —(CH₂)₂-phenylene-CH₂-, —(CH₂)₃-phenylene-(CH₂)₃—, —CH₂— phenylene-(CH₂)₃—, —(CH₂)₂-phenylene-(CH₂)₃—, —(CH₂)₃-phenylene-(CH₂)₂—, or —(CH₂)₃-phenylene-CH₂—.
 34. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the LIN represents 1,4-piperazinylene, spiro-cycloalkylene or 1,3-dialkynylene group.
 35. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 34, wherein the LIN represents:


36. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 35, wherein the LIN represents:

and the group A is C(O).
 37. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, which is selected from the group consisting of: 4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3,6,9,12,15-pentaoxaoctadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,7,10,13,16-pentaoxanonadecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-7-oxoheptanamide; 7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)-7-oxoheptanamide; 3-(4-(8-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-8-oxooctyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)heptanamide; 4-((8-(4-(6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)-1H-1,2,3-triazol-1-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)thio)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl) sulfinyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl) sulfonyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((12-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-12-oxododec-5-yn-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl) amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl) amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy) propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-11-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) amino)-3-methoxyphenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) amino)-3-methoxyphenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)propanamide; 4-((2-(2-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)propoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(2-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)propoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino) acetamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)butanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)pentanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)hexanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)heptanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)heptanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanamide; 4-((7-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl) amino)heptyl) amino)-2-(2, 6-dioxopiperidin-3-yl) isoindoline-1,3-dione; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)amino)heptanamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanediamide; (2S,4R)-1-((S)-2-(2-(2-(2-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide; N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)succinamide; 4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide; (2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-1-oxo-6, 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6, 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide; 8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 8-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)amino)hexanamide; 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(9-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide; (2S,4R)-1-((S)-2-(9-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide; (2S,4R)-1-((S)-2-(4-(4-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(4-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-((2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carbonyl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl) amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-11-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(11-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-11-yl)-3-oxopropoxy)ethyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((15-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(9-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-9-oxononyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(9-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-9-oxononyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-8-oxooctanamide; 4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((12-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((16-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-116-oxohexadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)-8-oxooctanamide; 4-((5-(4-(6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)-1H-1,2,3-triazol-1-yl)pentyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)thio)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)sulfinyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)sulfonyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1-(5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)urea; 4-(((E)-10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-10-oxodec-4-en-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5,6-dihydroxy-10-oxodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((7-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxohept-3-yn-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (2S,4R)-1-((S)-2-(4-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(4-(5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentanamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-16-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-19-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-22-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl) amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-((8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (2S,4R)-4-hydroxy-1-((S)-2-(13-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-13-oxotridecanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 2-(2,6-dioxopiperidin-3-yl)-4-((12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl) amino)-1,3,5-triazin-2-yl) amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-11-yl)-12-oxododecyl)amino)isoindoline-1,3-dione; 3-(4-((12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-12-oxododecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-12-oxododecanamide; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N13-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyltridecanediamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-17-methyl-4,16,19-trioxo-7,10,13-trioxa-3,17-diazanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 2-((2-((1-(N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N8-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N8-methyloctanediamide; 2-((2-((1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-13-methyl-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyladipamide; (2S,4R)-1-((S)-2-(6-((1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)amino)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-17-(tert-butyl)-2-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3,15-dioxo-6,9,12-trioxa-2,16-diazaoctadecan-18-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyldodecanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-12-((2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl) amino)-N-methyldodecanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N12-(2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)-N1-methyldodecanediamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide; (2S,4R)-1-((S)-2-(13-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-13-oxotridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(13-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)tridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-(13-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-11-yl)-3,3-dimethyl-1-oxobutan-2-yl) amino)-13-oxotridecyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7, 10-trioxa-14-azaheptadecyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-(13-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-13-oxotridecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-((S)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5-oxo-7,11,14-trioxa-4-azaheptadecan-17-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; and 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide.
 38. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, which is selected from the group consisting of: 3-(4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoine-1,3-dione; 3-(4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)ethoxy)ethoxy)ethoxy)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino) acetamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)butanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)pentanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)hexanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-methylbutanamide; 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl) amino)butyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)amino)butyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide; N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide; (2S,4R)-1-((S)-2-(8-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((8-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)octyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) amino)-3-methoxyphenyl)piperidin-4-yl) amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-11-oxoundecyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)undecyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 3-(4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione; 3-(4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-11-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 3-(4-((2-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)phenethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 8-(4-((2-(2,6-dioxopiperidin-3-yl)-11-oxoisoindolin-4-yl)glycyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; (2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6, 1-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)propanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)ethoxy)ethoxy)propanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6, 1-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamide; N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide; (2S,4R)-1-((S)-2-(2-(2-(2-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide; N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide; 8-(4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; 8-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((18-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((5-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((7-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)_(1,3,5)-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((15-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino) 1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((18-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino) 1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino) 1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione; 3-(4-((2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl) amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)—S-oxopentanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(7-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(8-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(9-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(10-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 2-((2-((1-(N-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadecan-18-amide; 2-((2-((1-(N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; 2-((2-((1-(N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide; (2S,4R)-1-((S)-2-(tert-butyl)-14-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-12-methyl-4,11,14-trioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-16-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-14-methyl-4,13,16-trioxo-7,10-dioxa-3,14-diazahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13-tetraoxahexadecanediamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13,16-pentaoxanonadecanediamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylsuccinamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylglutaramide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyladipamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylheptanediamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyloctanediamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylnonanediamide; N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyldecanediamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-N-methylpropanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-methylpropanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyl-3,6,9,12,15-pentaoxaoctadecan-18-amide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylacetamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylpropanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylpentanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylhexanamide; N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylheptanamide; (2S,4R)-1-((S)-12-(tert-butyl)-2-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3,10-dioxo-5,8-dioxa-2,11-diazatridecan-13-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13,16-pentaoxanonadecanediamide; N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylsuccinamide; N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyloctanediamide; N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyldecanediamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl) 1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl) amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(4-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(10-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7, 10-trioxa-14-azaheptadecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; and 6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide.
 39. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
 40. The pharmaceutical composition according to claim 39, further comprising at least one additional agent for treating and/or preventing cancer.
 41. A method for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
 42. The method according to claim 41, wherein the cancer is selected from the group consisting of lung cancer, lymphoma, inflammatory myofibroblastic tumor (IMT), colorectal cancer, brain tumor, acute myeloid leukemia, and ovarian cancer.
 43. The method according to claim 41, wherein the cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, EGFR-mutated non-small cell lung cancer, diffuse large B-cell lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, glioma, and glioblastoma.
 44. The method according to claim 42, wherein the lung cancer is a lung adenocarcinoma.
 45. The method according to claim 41, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject by at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, Pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration. 